Osmotic dosage forms comprising deutetrabenazine and methods of use thereof

ABSTRACT

Provided herein are osmotic dosage forms containing deutetrabenazine for use in the treatment of, e.g., hyperkinetic movement disorders. When orally administered to a subject on a once-daily basis, the dosage forms provide a favorable pharmacokinetic profile for the active agent indicating treatment efficacy over an extended period of time.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. application Ser. No.17/344,271, filed Jun. 10, 2021, which claims the benefit of U.S.Provisional Application Nos. 63/037,369, filed Jun. 10, 2020,63/037,953, filed Jun. 11, 2020, and 63/044,451 filed Jun. 26, 2020, theentireties of which are incorporated by reference herein.

TECHNICAL FIELD

The present disclosure pertains to osmotic dosage forms and methods ofuse of those dosage forms for treating hyperkinetic movement disordersderiving from conditions such as Huntington's disease, tardivedyskinesia, Tourette syndrome, levodopa-induced dyskinesia anddyskinesia in cerebral palsy.

BACKGROUND

Deutetrabenazine((RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one)is a vesicular monoamine transporter type 2 (VMAT2). The biologicallyactive metabolites formed from deutetrabenazine(alpha-dihydrodeutetrabenazine [α-deuHTBZ] andbeta-dihydrodeutetrabenazine [β-deuHTBZ]), together identified as“deuHTBZ”, are potent inhibitors of VMAT2 binding. Deutetrabenazineexhibits an increased half-life of its active metabolites, relative totetrabenazine (e.g., U.S. Pat. No. 8,524,733).

Deutetrabenazine is approved by the U.S. Food and Drug Administrationunder the tradename AUSTEDO® for the treatment of chorea (involuntarymuscle movements) associated with Huntington's disease (HD) and for thetreatment of tardive dyskinesia (TD) in adults. AUSTEDO® dosage formsare orally administered twice-daily (bid), for total daily doses of 12mg or above of deutetrabenazine.

One factor affecting gastrointestinal absorption of orally administereddrugs is the rate at which drug is released from the dosage form. Drugrelease rates for oral dosage forms are typically measured as rate ofdissolution in vitro, i.e., a quantity of drug released from the dosageform per unit time for example, in a FDA approved system. Such systemsinclude, for example, United States Pharmacopeia (USP) dissolutionapparati I and II.

The therapeutic window of a drug is the time period when the plasma drugconcentration is within the therapeutically effective plasma drugconcentration range. Because the plasma drug concentration declines overtime, however, multiple doses of drug dosage form must be administeredat appropriate intervals to ensure that the plasma drug concentrationremains within or, again rises to, the therapeutic window. At the sametime, however, there is a need to avoid or minimize plasma drugconcentrations that result in undesirable side effects.

Several dosage forms comprising deutetrabenazine are disclosed in U.S.Pat. No. 9,296,739. A dosage form that can deliver deutetrabenazine in acontrolled manner over an extended period of time would enable a moreadvantageous dosing regimen, e.g., one that would permit once-daily (qd)administration while maintaining the treatment effects currentlyrealized by AUSTEDO®. A need exists for such alternative dosage forms.

SUMMARY

Disclosed herein are osmotic dosage forms for once daily administrationof deutetrabenazine to a subject in need thereof comprising:

-   -   a. a tablet core comprising an active layer comprising an amount        of deutetrabenazine microparticles and a push layer;    -   b. a semipermeable layer surrounding the tablet core; and    -   c. a port extending through the semipermeable layer into the        tablet core.

Further disclosed herein are methods of treating a hyperkinetic movementdisorder in a subject comprising: administering on a once daily basis tothe subject an osmotic dosage form disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides an illustration of an osmotic dosage form incross-section.

FIG. 2a and FIG. 2b provide flowcharts of the general manufacturingprocesses for osmotic dosage forms according to the present disclosure.

FIG. 3a and FIG. 3b are graphs showing concentration (pg/mL) ofdeutetrabenazine vs. time (hours, “h”) in subjects administered 12 mgAUSTEDO® tablet bid (“R”) or an osmotic dosage form containing 24 mgdeutetrabenazine qd (“T2A”). FIG. 3a shows direct scale for meanconcentration, and FIG. 3b shows a log scale for mean concentration.

FIG. 4a and FIG. 4B are graphs showing concentration (pg/mL) of α- andβ-deuHTBZ (total deuHTBZ) vs. time (hours, “h”) in subjects administered12 mg AUSTEDO® tablet bid (“R”) or an osmotic dosage form containing 24mg deutetrabenazine qd (“T2A”). FIG. 4a shows direct scale for meanconcentration, and FIG. 4b shows a log scale for mean concentration.

FIG. 5 is a diagram summarizing the food effect study described inExample 4.

DETAILED DESCRIPTION

The present subject matter may be understood more readily by referenceto the following detailed description, which forms a part of thisdisclosure. It is to be understood that this invention is not limited tothe specific methods, conditions or parameters described and/or shownherein, and that the terminology used herein is for the purpose ofdescribing particular embodiments by way of example only and is notintended to be limiting of the claimed invention.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present application shall have the meanings that arecommonly understood by those of ordinary skill in the art. Further,unless otherwise required by context, singular terms shall includepluralities and plural terms shall include the singular.

As employed above and throughout the disclosure, the following terms andabbreviations, unless otherwise indicated, shall be understood to havethe following meanings.

In the present disclosure the singular forms “a”, “an”, and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “acompound” is a reference to one or more of such compounds andequivalents thereof known to those skilled in the art, and so forth. Theterm “plurality”, as used herein, means more than one. When a range ofvalues is expressed, another embodiment includes from the one particularand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it isunderstood that the particular value forms another embodiment. Allranges are inclusive and combinable.

As used herein, the terms “compound”, “drug”, “pharmacologically activeagent”, “active agent”, or “medicament” are used interchangeably hereinto refer to a compound or compounds or composition of matter which, whenadministered to a subject (human or animal) induces a desiredpharmacological and/or physiologic effect by local and/or systemicaction. The active agent is preferably deutetrabenazine, as disclosedherein.

As used herein, “dosage form” refers to a drug form having osmoticproperties and able to release active agent over an extended period, forexample, the dosage form releases not more than 60 wt % of the activeagent in the dosage form for 8 hours after administration. The activeagent is preferably deutetrabenazine, as disclosed herein.

As used herein, the term “drug formulation” refers to a solution orsuspension of the drug, optionally with excipients, formed in situ underaqueous conditions of the dosage form. The active agent is preferablydeutetrabenazine, as disclosed herein.

The terms “port” or “exit port”, used interchangeably, refer to meansand methods suitable for exit of the drug or the drug formulation fromthe core of the dosage form, for example, any hole, passage, channel orsimilar opening though which the drug or the drug formulation in thecore of the dosage form may exit. Other expressions of such terminclude, for example, exit means, orifice or hole.

As used herein, the terms “treatment” or “therapy” (as well as differentforms thereof) include preventative (e.g., prophylactic), curative, orpalliative treatment. As used herein, the term “treating” includesalleviating or reducing at least one adverse or negative effect orsymptom of a condition, disease or disorder. This condition, disease ordisorder may refer to hyperkinetic movement disorder, such as, but notlimited to, Huntington's disease, tardive dyskinesia, Tourette syndrome,dystonia, dyskinesia in cerebral palsy and Parkinson's diseaselevodopa-induced dyskinesia.

The term “administering” means providing to a patient a pharmaceuticalcomposition or dosage form (used interchangeably herein) disclosedherein.

The terms “subject”, “individual”, and “patient” are usedinterchangeably herein, and refer to a human, to whom treatment,including prophylactic treatment, with a dosage form disclosed herein,is provided.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or excipients which are, within the scope of soundmedical judgment, suitable for contact with the tissues of human beingswithout excessive toxicity, irritation, allergic response, or otherproblem complications commensurate with a reasonable benefit/risk ratio.

The presently disclosed dosage forms may include “derivatives” ofcertain dosage form materials or ingredients, such as derivatives ofcellulose or starch. As used herein, a “derivative” of a material mayrefer to a synthetic or semi-synthetic product of that material. Forexample, in the case of cellulose, a derivative can refer tosemi-synthetic cellulose products such as cellophane, rayon, andcellulose acetate, cellulose esters, and cellulose ethers.

“Microparticles” refers to particles, for example deutetrabenazineparticles, with a particle size (i.e. diameter) below 1 mm. In oneembodiments, the median diameter (D₅₀) of the microparticles is fromabout 0.05 to about 100 μm. In another embodiment, D₅₀ of themicroparticles is from about 0.05 to about 50 μm. In another embodiment,the D₅₀ of the microparticles is from about 1 μm to about 30 μm, orabout 1 μm to about 25 μm, or about 5 μm to about 30 μm, or about 1 μmto about 20 μm, or about 5 μm to about 25 μm, or about 10 μm to about 20μm. In one embodiment, the deutetrabenazine microparticles have aparticle size distribution of about 1 μm to about 30 μm in diameter. Inanother embodiment, the deutetrabenazine microparticles have a D₉₀ of 15μm (i.e. 90% of the particles have a diameter less than or equal to 15um). In another embodiment, the deutetrabenazine microparticles have aD₅₀ 10 μm (i.e. 50% of the particles have a diameter greater than 10 umand 50% of the particles have a diameter less than or equal to 10 um).In yet another embodiment, the deutetrabenazine microparticles have aD₁₀ of 3 μm (i.e. 10% of the particles have a diameter less than 3 um).

The terms D₉₀, D₅₀ or D₁₀ are well understood in the art. The particlesize distribution of the microparticles (i.e. the diameters) can bedetermined by one with skill in art using conventional methods, forexample, dynamic or static light-scattering of an aqueous dispersion ofthe microparticle composition. The D₉₀ and D₁₀ values, like the D₅₀value, can be calculated from the particle size distribution of themicroparticles.

Osmotic dosage forms, in general, utilize osmotic pressure to generate adriving force for imbibing fluid, for example, from the gastrointestinal(GI) tract, into a compartment formed, at least in part, by asemipermeable wall, layer or membrane that permits free diffusion offluid but not drug or osmotic agent(s), if present. A constant rate ofdrug release can be achieved by designing the system to provide arelatively constant osmotic pressure and having suitable exit means forthe drug formulation to be released at a rate that corresponds to therate of fluid imbibed as a result of the relatively constant osmoticpressure. Without being limited to theory, osmotic systems may operateindependently of pH and thus, operation continues at theosmotically-determined rate throughout an extended time period even asthe dosage form transits the GI tract and encounters differingmicroenvironments having significantly different pH values.

An example of one type of osmotic device comprises two component layerswithin a compartment (herein referred to as, and used interchangeablywith, a core) formed by a semipermeable wall. One component layer(herein referred to as an active layer) comprises drug (i.e.deutetrabenazine) in a mixture with an excipient(s) and the secondcomponent layer (herein referred to as a push layer) comprises anosmotically active agent(s), optionally in a mixture with excipients butdoes not contain drug. This core is further coated by the semipermeablewall, which permits entry of aqueous fluid, i.e. from the GI system,into the core. Without wishing to be limited to theory, as fluid isimbibed into the dosage form, the active layer forms a drug formulationand the osmotic agent(s) in the push layer swell and push against thedrug formulation to thereby facilitate release of the drug formulationat a substantially constant rate. See, e.g., U.S. Pat. Nos. 4,327,725;4,612,008; 4,783,337; and 5,082,668.

Although constant-release dosage forms have been proven effective formany different drug therapies, there are clinical situations where thesehave not been entirely satisfactory. It has been observed that for somepatients, the therapeutic effectiveness of the drug decreases below thetherapeutically effective threshold before the end of the desiredtherapy period despite the maintenance of substantially constant drugrelease that would be expected to provide continued effectiveness.

It has been surprisingly discovered that oral dosage forms comprisingdeutetrabenazine that exhibit a desirable rate of release and hence adesirable pharmacokinetic profile for an extended time can be achieved.In some embodiments, the presently disclosed osmotic dosage formsprovide a pharmacokinetic profile when administered orally to a subjecton a once daily basis (q.d.) that is comparable, e.g., bioequivalent, tothat of the AUSTEDO® dosage forms administered b.i.d. In certainembodiments, the osmotic dosage forms provide an in vivo plasma profilefor total deuHTBZ at steady state that includes a mean AUC₀₋₂₄ of about410,000 to 800,000 h*pg/mL, and a mean C_(max) of less than about 40,000pg/mL.

The osmotic dosage forms of the present disclosure include a tablet corecontaining at least a push layer and an active layer, wherein the activelayer includes deutetrabenazine and one or more excipient for forming adrug formulation when hydrated, and wherein the push layer includes atleast one osmotic agent and one or more excipient. Both the push layerand active layer are contained within a tablet core at least partiallysurrounded by a semipermeable layer having a port that functions as anexit means for drug formulation release from the tablet core. In someembodiments, the two layers are compressed into a bilayer tablet coresurrounded by a semipermeable membrane and further having a suitableorifice for drug release there through.

An embodiment of an oral osmotic dosage form disclosed herein isillustrated in the cross section in FIG. 1. The components are not drawnto scale. The dosage form (2) comprises a bilayer tablet core. The corecomprises an active layer (4), containing drug, e.g. deutetrabenazine,and one or more active layer excipients, and a push layer (6),containing at least one osmotic agent along with one or more push layerexcipients. At least a portion of the active layer forms a drugformulation upon exposure to an aqueous milieu. Suitable active layerand push layer excipients are known in the art and include diluents,carriers, binders, fillers, control release agents and processing aids.A semipermeable membrane (8) surrounds the bilayer tablet core and asuitably sized port (10) that extends from the semipermeable membraneinto the active layer (4) is present to permit drug formulation to bereleased from within the tablet core. As illustrated, the dosage formmay be longitudinally compressed and the port (10) present on the sideof the dosage form comprising the active layer. In other embodiments,the dosage form is compressed along the lateral axis of the dosage form,and the port is present on one end of the dosage form. In allembodiments, more than one port may be present. Through cooperation ofthe osmotic dosage form components and in the presence of an aqueousmilieu, drug formulation is released from the active layer through theport at a desired release rate for an extended time. Although not shownin FIG. 1, an optional immediate-release layer (immediate releasecoating), external to the semipermeable layer, including further drug(ie deutetrabenazine microparticles) may be further provided, ifdesired, as described elsewhere herein.

In one embodiment, the invention provides an osmotic dosage form foronce daily administration to a subject in need thereof comprising:

-   -   a. a tablet core comprising an active layer comprising an amount        of deutetrabenazine microparticles and a push layer;    -   b. a semipermeable layer surrounding the tablet core; and    -   c. a port in the semipermeable layer extending to the tablet        core.

The active layer contained within the tablet core includesdeutetrabenazine and pharmaceutically acceptable active layerexcipients. In preferred embodiments, the deutetrabenazine is providedas deutetrabenazine microparticles. The deutetrabenazine microparticlesmay be present in the active layer in an amount of about 2% to 20%(i.e., about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, 20%), by weight (% w/% w) based on the totalweight of the active layer.

In a specific embodiment, the active layer excipient comprises an activelayer control release agent. In an embodiment of the invention, theactive layer control release agent has a viscosity of about 50-150 mPas. In one specific embodiment, the active layer control release agenthas a viscosity of about 55-90 mPa s. In a preferred embodiment, theactive layer control release agent comprises a polyoxyethylene polymer,an ionic hydrogel, a hydrophilic polymer, a hydrophobic polymer or anymixture thereof. In another embodiment, the active layer control releaseagent comprises a polyoxyethylene polymer, which is polyethylene oxide.In yet another embodiment, the polyethylene oxide within the activelayer has an average molecular weight of 100,000 daltons to 500,000daltons. In some embodiments, the polyethylene oxide within the activelayer has an average molecular weight of about 200,000 daltons.

In another embodiment, the active layer control release agent is presentin the active layer in an amount of about 60% to about 98% by weight,based on the total weight of the active layer. In one specificembodiment, the active layer control release agent is present in theactive layer in an amount of about 70% to about 85% by weight, based onthe total weight of the active layer. In one specific embodiment, theactive layer control release agent is present in the active layer in anamount of about 80% to about 90% by weight, based on the total weight ofthe active layer. In one specific embodiment, the active layer controlrelease agent is present in the active layer in an amount of about 85%to about 95% by weight, based on the total weight of the active layer.

In one embodiment, the weight ratio of the amount of deutetrabenazinemicroparticles and the amount of active layer control release agent inthe active layer is 2:3-1:50. In one specific embodiment, the weightratio of the amount of deutetrabenazine microparticles and the amount ofactive layer control release agent in the active layer is 2:5-1:5. Inone specific embodiment, the weight ratio of the amount ofdeutetrabenazine microparticles and the amount of active layer controlrelease agent in the active layer is 1:4-1:9. In one specificembodiment, the weight ratio of the amount of deutetrabenazinemicroparticles and the amount of active layer control release agent inthe active layer is 1:5-1:19. In one specific embodiment, the weightratio of the amount of deutetrabenazine microparticles and the amount ofactive layer control release agent in the active layer is 1:5-1:10. Inone specific embodiment, the weight ratio of the amount ofdeutetrabenazine microparticles and the amount of active layer controlrelease agent in the active layer is 1:5-1:7. In one specificembodiment, the weight ratio of the amount of deutetrabenazinemicroparticles and the amount of active layer control release agent inthe active layer is 1:12-1:15. In one specific embodiment, the weightratio of the amount of deutetrabenazine microparticles and the amount ofactive layer control release agent in the active layer is 1:20-1:30.

Optional excipients within the active layer include antioxidants,binders, lubricants, colorants, and the like. Such excipients are wellknown among those of ordinary skill in the art. In some embodiments theactive layer comprises deutetrabenazine microparticles, an active layerexcipient and optionally one or more of an antioxidant, a binder, alubricant, a colorant, or any combination thereof.

In one embodiment, the active layer further comprises at least oneactive layer antioxidant. Preferably, the active layer antioxidantcomprises: tertiary butyl-4-methoxyphenol (mixture of 2 and 3-isomers),2,6-ditertiary butyl-p-cresol, propyl gallate,6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin),nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylatedhydroxytoluene or any mixture thereof. In one specific embodiment, theactive layer comprises a mixture of butylated hydroxyanisole andbutylated hydroxytoluene. In one embodiment, the active layerantioxidant may be present in the active layer in an amount of about0.001% to about 1% by weight, based on the total weight of the activelayer.

In one embodiment, the active layer further comprises an active layerbinder. In an embodiment, the active layer binder comprises hypromellose(hydroxypropyl methylcellulose), starch, gelatin, agar, natural andsynthetic gums and any mixture thereof. In another embodiment, theactive layer binder comprises hypromellose. In one embodiment, theactive layer binder may be present in the active layer in an amount ofabout 2% to about 20% by weight, based on the total weight of the activelayer.

In one embodiment, the active layer further comprises one or morepharmaceutically acceptable lubricant. Suitable lubricants include,without limitation, talc, starch, zinc stearate, aluminum stearate,magnesium stearate, calcium stearate, boric acid, sodium chloride,paraffin, stearic acid, low melting point waxes, hydrogenated vegetableoils and saturated fatty acid esters. In a specific embodiment, one ormore lubricants may be present in the active layer in an amount of about0.001% to about 0.2% by weight, based on the total weight of the activelayer.

In an embodiment, the active layer comprises deutetrabenazinemicroparticles, and an active layer control release agent having aviscosity of about 55-90 mPa s. In some embodiments, the active layercontrol release agent comprises polyethylene oxide. In yet anotherembodiment, the active layer comprises deutetrabenazine microparticles,polyethylene oxide and further comprises butylated hydroxyanisole,butylated hydroxytoluene, hypromellose and magnesium stearate.

The push layer contained within the tablet core comprises an osmoticagent which, without being bound to theory, acts as a fluid-attractingagent which swells when exposed to an aqueous milieu and pushes againstthe active layer enabling the flow of the drug formulation from withinthe dosage form out into an external environment. The osmotic agent, isdefined as, for example, a non-volatile species which is generallysoluble in water and create the osmotic gradient thereby enabling theosmotic inflow of water. Species which fall within the category ofosmotic agent include inorganic salts or carbohydrates. Non limitingexamples of osmotic agents are well known in the art and includemagnesium sulfate, magnesium chloride, potassium sulfate, sodiumchloride, sodium sulfate, lithium sulfate, sodium phosphate, potassiumphosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate,tartaric acid, raffinose, and various monosaccharides, oligosaccharidesand polysaccharides such as sucrose, glucose, lactose, fructose, anddextran, as well as mixtures of any one of these various species.

In one embodiment, the osmotic agent is present in the push layer in anamount of about 5% to about 50% by weight, based on the total weight ofthe dosage form. In an embodiment, the osmotic agent is present in thepush layer in an amount of about 5% to about 20% by weight, based on thetotal weight of the dosage form. In another embodiment, the osmoticagent is present in the push layer in an amount of about 8% to about 10%by weight, based on the total weight of the dosage form.

In one embodiment, the osmotic agent is present in the push layer in anamount of about 20% to about 40% by weight, based on the total weight ofthe push layer. In an embodiment, the osmotic agent is about 30% byweight, based on the total weight of the push layer.

The push layer further comprises one or more excipients, such as acontrol release agent. In one embodiment, the push layer comprises anosmotic agent and a push layer control release agent. Push layer controlrelease agents include polymers providing a swellable matrix uponcontact with water. In one embodiment, the push layer control releaseagent has a viscosity of about 5500-7500 mPa s.

Examples of a push layer control release agent include polyoxyethylenepolymers, ionic hydrogels, hydrophilic polymers, hydrophobic polymersand any mixture thereof. In one embodiment, the push layer controlrelease agent comprises a polyoxyethylene polymer, which is polyethyleneoxide. In another embodiment, the polyethylene oxide within the pushlayer has an average molecular weight of 1,000,000 daltons to 7,000,000daltons. In yet another embodiment, the polyethylene oxide within thepush layer has an average molecular weight of 5,000,000 daltons.

In one embodiment, the push layer control release agent is present inthe push layer in an amount of about 50% to about 80% by weight, basedon the total weight of the push layer. In another embodiment, the pushlayer control release agent is present in the push layer in an amount ofabout 60% to about 70% by weight, based on the total weight of the pushlayer.

In one embodiment, the weight ratio of the osmotic agent and the pushlayer control release agent in the push layer is 1:2-1:3.5 or about 1:2to 1:2.5.

The push layer optionally further contains other pharmaceuticallyacceptable excipients, e.g., for stabilizing the layer, providing colorfor tablet orientation, or the like. Exemplary excipients includebinders, colorants, and lubricants, and suitable examples of these typesof excipients are well known among those of ordinary skill in the art.

In one embodiment, the push layer further comprises a push layer binder.The push layer binder can be selected from hypromellose (hydroxypropylmethylcellulose), starch, gelatin, agar, natural and synthetic gums, andany mixture thereof. Preferably, the push layer binder is hypromellose.In one embodiment, the push layer binder is present in the push layer inan amount of about 2% to about 10% by weight, based on the total weightof the push layer. In another embodiment, the push layer binder ispresent in the push layer in an amount of about 3% to about 6% byweight, based on the total weight of the push layer.

Lubricants within the push layer can include any of the exemplarymaterials described supra in connection with the active layer. The pushlayer may also include a disintegrant such as cross-linkedpolyvinylpyrrolidone, corn starch, potato starch, smectite clay (e.gmagnesium aluminum silicate such as Veegum®), bentonite and citrus pulp.It may also be desirable to include stabilizers for the drug. Theseinclude, without limitation, sodium bisulfate and histidine HCl.

In one specific embodiment, the push layer comprises sodium chloride,polyethylene oxide, hydroxypropyl methylcellulose, a colorant, andmagnesium stearate.

The present osmotic dosage forms include a semipermeable layer thatsurrounds the tablet core, thereby enabling influx of fluid from anexternal fluid environment (e.g., a subject's gastrointestinal tract)into the tablet core while preventing efflux of drug from the core. Thesemipermeable layer is preferably formed of a material that does notadversely affect the patient, and is permeable to an external fluid suchas water and biological fluids. The selectively permeable materialsforming the semipermeable layer are insoluble in body fluids, and arenon-erodible or are bioerodible after a predetermined period withbioerosion corresponding to the end of the drug formulation releaseperiod. As used herein, “semipermeable layer”, “semipermeable wall” and“semipermeable membrane” are interchangeable.

Generally, semipermeable materials useful for forming the semipermeablelayer may have a fluid permeability of 10⁻⁵ to 10⁻¹ (cc mil/cm² hr atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the wall at the temperature of use. Suitable materials are knownin the art, see, e.g., U.S. Pat. Nos. 3,845,770 and 3,916,899.

Typical materials useful for forming the semipermeable layer includematerials known in the art including cellulose acetate, cellulosetriacetate, agar acetate, amylose triacetate, beta glucan acetate,cellulose diacetate, acetaldehyde dimethyl acetate, cellulose acetateethyl carbamate, polyamides, polyurethane, sulfonated polystyrenes,cellulose acetate phthalate, cellulose acetate methyl carbamate,cellulose acetate succinate, cellulose acetate dimethylaminoacetate,cellulose acetate ethyl carbamate, cellulose acetate chloroacetate,cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate,cellulose dipentanlate, cellulose acetate valerate, cellulose acetatesuccinate, cellulose propionate succinate, methyl cellulose, celluloseacetate p-toluene sulfonate, cellulose acetate butyrate, selectivelypermeable polymers formed by the coprecipitation of a polycation and apolyanion as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006; and 3,546,142.

In one embodiment, the semipermeable layer comprises water solublepolymers or water insoluble polymers including cellulose acetate,cellulose diacetate, cellulose triacetate, cellulose propionate,cellulose acetate butyrate; cellulose ethers including ethyl cellulose,agar acetate, amylose triacetate, betaglucan acetate, poly(vinyl methyl)ether copolymers, poly(orthoesters), poly acetals and selectivelypermeable poly(glycolic acid), poly(lactic acid) derivatives and anymixture thereof. Cellulose acetate includes cellulose acetate polymers(e.g. Eudragit®). In one embodiment, the semipermeable layer comprises awater insoluble polymer, which is present in an amount of about 80% toabout 99.9% by weight, based on the weight of the semipermeable layer.In another embodiment, the water insoluble polymer is about 85% to about95% by weight, based on the weight of the semipermeable layer.Preferably, the semipermeable layer comprises a water insoluble polymerwhich is cellulose acetate, comprising about 32%-40% acetyl content.

The semipermeable layer may further include a pore-forming agent or“pore former”. Pore forming agents include biocompatible materials thatwhen contacted with body fluids dissolve, disperse or degrade to createpores or channels in the semipermeable layer material. Typically, watersoluble organic and non-organic materials such as sugars (e.g., sucrose,dextrose), water soluble salts (e.g., sodium chloride, sodium phosphate,potassium chloride, and sodium carbonate), water soluble solvents suchas N-methyl-2-pyrrolidone and polyethylene glycol and water solublepolymers (e.g., carboxymethylcellulose, hydroxypropylcellulose, and thelike) can conveniently be used as pore formers. In one embodiment, thesemipermeable layer comprises, in addition to the water soluble polymeror water insoluble polymer, a pore-forming agent, which is selected fromwater soluble sugars, water soluble salts, water soluble solvents andwater soluble polymers or any mixture thereof. In a specific embodiment,the pore-forming agent is a water soluble solvent, which is polyethyleneglycol. In one embodiment, the pore-forming agent comprises about 0.1%to about 20% by weight of the semipermeable layer. Preferably, thepore-forming agent comprises about 8% to about 15% by weight of thesemipermeable layer. In one embodiment, the weight ratio of thesemipermeable layer and the tablet core is 1:8-1:10.

In one specific embodiment, the semipermeable layer comprises celluloseacetate and polyethylene glycol.

The present dosage forms include a port(s), independently of or inaddition to the pore-forming agent. The port is present within thesemipermeable layer and extends from external to the semipermeable layerinto the tablet core providing an exit means for the drug formulationfrom the active layer within the tablet core into the environmentexternal to the dosage form. The exit port(s) are formed by any meansknown in the art including mechanical drilling, laser drilling, erodingan erodible element, extracting, dissolving, bursting, or by leaching.For example, the port(s) may be formed by post-coating mechanical orthermal means or with a beam of light (e.g., a laser), a beam ofparticles, or other high-energy source, or may be formed in situ byrupture of a small portion of the coating. Such rupture may becontrolled by intentionally incorporating a relatively small weakportion into the coating. Exit port(s) may also be formed in situ byerosion of a plug of water-soluble material or by rupture of a thinnerportion of the coating over an indentation in the core. Exit port(s) maybe formed by coating the core such that one or more small regionsremains uncoated. In addition, the exit port(s) can be a large number ofholes or pores that may be formed during coating. The exit port(s) canbe a pore formed by leaching sorbitol, lactose or the like from a wallor layer as disclosed in U.S. Pat. No. 4,200,098. This patent disclosespores of controlled-size porosity formed by dissolving, extracting, orleaching a material from a wall, such as sorbitol from celluloseacetate. A preferred form of laser drilling is the use of a pulsed laserthat incrementally removes material from the semipermeable layer to thedesired depth to form the exit port. In certain embodiments, a port, ora plurality of ports, can be formed, for example, by leaching a memberselected from the group consisting of sorbitol, lactose, fructose,glucose, mannose, galactose, talose, sodium chloride, potassiumchloride, sodium citrate and mannitol to provide a uniform-releasedimensioned exit port. The exit means can have any shape, such as round,triangular, square, elliptical and the like for the uniform metered doserelease of a drug formulation from the dosage form. The osmotic dosageform can be constructed with one or more exits ports in spaced-apartrelation or one or more surfaces of the osmotic dosage form. Such exitsand equipment for forming such exits are disclosed, for example, in U.S.Pat. Nos. 3,916,899 and 4,088,864.

In one embodiment, the port has a diameter of from about 0.1 mm to about1 mm. In another embodiment, the port has a diameter of from about 0.4mm to about 0.8 mm.

In some embodiments, the dosage form further includes one or more sealcoatings for example, in order to ensure integrity of one or moresubparts of the present dosage forms. In one embodiment, the tablet corecomprises a seal coating immediately external to the tablet core. Forexample, a tablet core seal coating may be applied to the outer surfaceof the compressed, layered tablet core prior to application of thesemipermeable layer. In certain embodiments, the tablet core comprises asemipermeable layer immediately external to the tablet core and a sealcoating immediately external to the semipermeable layer. For example, asemipermeable layer seal coating may be applied to the outer surface ofthe dosage form following application of the semipermeable membrane tothe tablet core. Seal coating materials can include binders, numeroustypes of which are disclosed supra. In embodiments comprising sealcoating between the core and immediately external to the semipermeablemembrane, the port will extend from external to the seal coating throughall layers and into the core.

In one embodiment, a tablet core seal coat is applied to the outersurface of the tablet core.

In one embodiment, a semipermeable layer seal coat applied to the outersurface of the semipermeable layer.

In one embodiment, the tablet core seal coat and or the semipermeablelayer seal coat comprises a binder which can be selected from:hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar,natural and synthetic gums and any mixture thereof. In anotherembodiment, the tablet core seal coat binder and or the semipermeablelayer seal coat binder is hypromellose.

In one embodiment, the total amount of the binder within the dosage formis from about 0 to about 20% by weight, based on the total weight of thedosage form. In another embodiment, the total amount of the binderwithin the dosage form is form about 5% to about 20% by weight, based onthe total weight of the dosage form. In yet another embodiment, thetotal amount of the binder within the dosage form is about 8% to about10% by weight, based on the total weight of the dosage form or about 10%to about 20% by weight, based on the total weight of the dosage form.

The absolute amount of deutetrabenazine in the active layer of thepresent osmotic dosage forms will depend on the dosage strength of theparticular embodiment. As described more fully below, the dosage formsmay further include an immediate release amount of deutetrabenazinemicroparticles that is external to the active layer, preferably externalto the semipermeable membrane layer.

In one embodiment, the dosage forms disclosed herein further comprise animmediate release coating comprising a second amount of deutetrabenazinemicroparticles, external to the semipermeable membrane or external tothe semipermeable layer seal coating applied thereto.

In one embodiment, the immediate release coating comprises about 0.1% toabout 25% by weight deutetrabenazine microparticles, based on the totalweight of the dosage form. In another embodiment, the immediate releasecoating comprises about 0.2% to about 5% by weight deutetrabenazinemicroparticles, based on the total weight of the dosage form. In anotherembodiment, the immediate release coating comprises about 0.3% to about2% by weight deutetrabenazine microparticles, based on the total weightof the dosage form In another embodiment, wherein the dosage formcomprises a total of 24 mg of deutetrabenazine microparticles, theimmediate release coating comprises about 1% to about 2% by weightdeutetrabenazine microparticles, based on the total weight of the dosageform. In another embodiment, wherein the dosage form comprises a totalof 12 mg of deutetrabenazine microparticles, the immediate releasecoating comprises about 0.5% to about 1% by weight deutetrabenazinemicroparticles, based on the total weight of the dosage form. In yetanother embodiment, wherein the dosage form comprises a total of 6 mg ofdeutetrabenazine microparticles, the immediate release coating comprisesabout 0.1% to about 0.5% by weight deutetrabenazine microparticles,based on the total weight of the dosage form.

In one embodiment, at least 70% of the total amount of deutetrabenazinemicroparticles in the dosage form is present within the active layer. Inanother embodiment, 70% to 100% of the total amount of deutetrabenazinemicroparticles in the dosage form, is present within the active layer.In yet another embodiment, about 70% to 80% of the total amount ofdeutetrabenazine microparticles in the present dosage forms is presentwithin the active layer. In some embodiments of the osmotic dosageforms, deutetrabenazine is present solely in the active layer.

In the embodiments in which the osmotic dosage forms comprise animmediate release coating, comprising up to about 30% of the totalamount of deutetrabenazine microparticles in the dosage form. In oneembodiment, about 8% to 30% of the total amount of deutetrabenazinemicroparticles in the dosage form is present within an immediate releasecoating. In one embodiment of the invention, about 70% to about 80% ofthe total amount of deutetrabenazine microparticles in the presentdosage forms is present within the active layer and about 20% to about30% of the total amount of deutetrabenazine microparticles in the dosageform, is present within an immediate release coating.

The dosage form of any embodiment of the invention comprises a totalamount of deutetrabenazine microparticles of from about 6 mg to about 48mg. In one embodiment, the total amount of deutetrabenazinemicroparticles in the dosage form is about 6 mg. In one embodiment, thetotal amount of deutetrabenazine microparticles in the dosage form isabout 12 mg. In another embodiment, the total amount of deutetrabenazinemicroparticles in the dosage form is about 24 mg. In yet anotherembodiment, the total amount of deutetrabenazine microparticles in thedosage form is about 36 mg. Yet in another embodiment, the total amountof deutetrabenazine microparticles in the dosage form is about 48 mg.

According to the disclosure, the total amount of deutetrabenazine or thetotal daily dose of deutetrabenazine, used herein interchangeably, isadministered to a subject as a one dose a day (QD). Depending on thetotal daily dose, one or more than one (multiple) dosage forms may beadministered to a subject at one dose. Preferably, a single dosage formis administered at one dose. In one embodiment, the total daily dose ofdeutetrabenazine is from 12 mg to 48 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 12 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 18 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 24 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 30 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 36 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 42 mg. In one embodiment, the totaldaily dose of deutetrabenazine is 48 mg.

Patients being treated with deutetrabenazine twice daily (bid) may beswitched to deutetrabenazine once daily (qd), at the same total dailydose, the day following a last dose of deutetrabenazine bid.

Patients being treated with deutetrabenazine once daily (qd) may beswitched to deutetrabenazine twice daily (bid), at the same total dailydose, the day following a last dose of deutetrabenazine qd.

Patients being treated with tetrabenazine may be switched todeutetrabenazine once daily osmotic dosage form disclosed herein (qd),the day following a last dose of tetrabenazine.

In one embodiment, the total amount of deutetrabenazine microparticlespresent within the dosage form is about 0.5% to about 15% by weight,based on the total weight of the osmotic dosage form. In anotherembodiment, the total amount of deutetrabenazine microparticles presentwithin the dosage form is about 1% to about 10% by weight, based on thetotal weight of the dosage form. In another embodiment, wherein thedosage form comprises a total of 6 mg of deutetrabenazinemicroparticles, the total amount of deutetrabenazine microparticlespresent within the dosage form is about 0.5% to about 3% by weight,based on the total weight of the dosage form. In another embodiment,wherein the dosage form comprises a total of 12 mg of deutetrabenazinemicroparticles, the total amount of deutetrabenazine microparticlespresent within the dosage form is about 1% to about 5% by weight, basedon the total weight of the dosage form. In another embodiment, whereinthe dosage form comprises a total of 24 mg of deutetrabenazinemicroparticles, the total amount of deutetrabenazine microparticlespresent within the dosage form is about 5% to about 10% by weight, basedon the total weight of the dosage form.

In addition to an amount of deutetrabenazine microparticles, theimmediate release coating may further include one or morepharmaceutically acceptable excipients such as an antioxidant, a binder,and a surfactant or any combination thereof. Antioxidants, binders, andsurfactants may be selected from a wide variety of choices known amongthose skilled in the art. Exemplary antioxidants and binders aredisclosed supra in connection with the other components of the presentdosage forms. Surfactants may include, but are not limited to, esters ofpolyhydric alcohols such as glycerol monolaurate, ethoxylated castoroil, polysorbates, esters or ethers of saturated alcohols such asmyristyl lactate (e.g. Ceraphyl®50), andpolyoxyethylene/polyoxypropylene block copolymers, such as Pluronic®.

In one embodiment, the immediate release coating further comprises anantioxidant which can be selected from: tertiary butyl-4-methoxyphenol(mixture of 2 and 3-isomers), 2,6-ditertiary butyl-p-cresol, propylgallate, 6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin),nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole, butylatedhydroxytoluene and any mixture thereof. In another embodiment, theimmediate release coating comprises a mixture of butylatedhydroxyanisole, and butylated hydroxytoluene. In another embodiment, theimmediate release coating comprises deutetrabenazine microparticles,butylated hydroxyanisole, butylated hydroxytoluene, hypromellose andpolysorbate 80.

In one embodiment, provided is an osmotic dosage form for once dailyadministration of deutetrabenazine to a subject in need thereofcomprising:

-   a. a tablet core comprising:    -   i. an active layer comprising an amount of deutetrabenazine        microparticles and an active layer control release agent        comprising a polymer having a viscosity of about 55-90 mPa s, an        active layer antioxidant, an active layer binder;    -   ii. a push layer comprising an osmotic agent and a push layer        control release agent comprising a polymer having a viscosity of        about 5500-7500 mPa s and a push layer binder;-   b. a tablet core seal coat comprising a binder on the outer surface    of the tablet core;-   c. a semipermeable layer comprising a water insoluble polymer and a    pore-forming agent surrounding the tablet core seal coat;-   d. a semipermeable layer seal coat comprising a binder on the outer    surface of the semipermeable layer;-   e. an immediate release coating comprising a second amount of    deutetrabenazine microparticles and an immediate release coating    antioxidant on the outer surface of the semipermeable layer seal    coat; and-   f. a port in the semipermeable layer seal coat reaching the tablet    core.

In some embodiments, provided is an osmotic dosage form according to anyone of the embodiments of the invention, wherein not more than 15% ofthe drug formulation is released within 2 hours and/or wherein not morethan 60% of the drug formulation is released within 8 hours, when thedosage form is tested in 500 mL acid phosphate buffer at pH 3.0 using aUSP II dissolution apparatus.

Further provided, herein is a method of treating a hyperkinetic movementdisorder in a subject comprising orally administering, on a once dailybasis to the subject, an osmotic dosage form according to any one of theembodiments of the invention. Further provided is an osmotic dosage formaccording to any one of the embodiments disclosed herein for oral once aday use in treating a hyperkinetic movement disorder in a subject.

In some embodiments, the movement disorder is selected from chorea,akathisia, dyskinesia, tremor, or tic. In some embodiments, the movementdisorder is selected from chorea associated with Huntington's disease,tardive dyskinesia, a tic associated with Tourette syndrome, Parkinson'sdisease levodopa-induced dyskinesia or dyskinesia in cerebral palsy.

In certain embodiments, the osmotic dosage form according to any one ofthe embodiments disclosed herein, is administered with food.

In certain embodiments, the osmotic dosage form according to any one ofthe embodiments disclosed herein, is administered under fastingconditions.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 6 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean AUC_(0-inf) of about 91,250 to 142,750 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 6 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean C_(max) of less than about 4,600 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 12 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean AUC_(0-inf) of about 182,500 to 285,500 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 12 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean C_(max) of less than about 9,200 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 24 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean AUC_(0-inf) of about 365,000 to 571,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 24 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean C_(max) of less than about 18,400 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 36 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean AUC_(0-inf) of about 547,500 to 856,500 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 36 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean C_(max) of less than about 27,600 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 48 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean AUC_(0-inf) of about 730,000 to 1,142,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein singledose administration of the osmotic dosage form, which comprises a totalamount of 48 mg of deutetrabenazine microparticles, provides an in vivoplasma profile for total α- and β-dihydrodeutetrabenazine that includesa geometric mean C_(max) of less than about 36,800 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 6 mg ofdeutetrabenazine microparticles provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean AUC₀₋₂₄ of about 102,500 to 200,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 6 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean C_(max) of less than about 10,000 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 12 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean AUC₀₋₂₄ of about 205,000 to 400,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 12 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean C_(max) of less than about 20,000 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 24 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean AU₀₋₂₄ of about 410,000 to 800,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 24 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean C_(max) of less than about 40,000 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 36 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean AUC₀₋₂₄ of about 615,000 to 1,200,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 36 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean C_(max) of less than about 60,000 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 48 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean AUC₀₋₂₄ of about 820,000 to 1,600,000 h*pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprisingorally administering to the subject a once daily osmotic dosage formaccording to any one of the embodiments of the invention wherein theosmotic dosage form which comprises a total amount of 48 mg ofdeutetrabenazine microparticles, provides an in vivo plasma profile fortotal α- and β-dihydrodeutetrabenazine at steady state that includes amean C_(max) of less than about 80,000 pg/mL.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder comprising: administering an osmoticdosage form according to any one of the embodiments of the invention,wherein not more than 15% of the drug formulation is released after 2hours when tested in 500 mL acid phosphate buffer at pH 3.0 using a USPII dissolution apparatus.

In one embodiment, the invention provides a method of treating ahyperkinetic movement disorder in a subject in need thereof comprising:administering to the subject a once daily osmotic dosage form accordingto any one of the embodiments of the invention, wherein not more than60% of the drug formulation is released within 8 hours when tested in500 mL acid phosphate buffer at pH 3.0 using a USP II dissolutionapparatus.

In some embodiments, the invention provides a method of treating ahyperkinetic movement disorder comprising: administering an osmoticdosage form according to any one of the embodiments of the invention,wherein not more than 15% of the drug formulation is released after 2hours and wherein not more than 60% of the drug formulation is releasedwithin 8 hours when tested in 500 mL acid phosphate buffer at pH 3.0using a USP II dissolution apparatus.

Further provided is a method of transitioning a human subject beingtreated with a total daily dose of deutetrabenazine twice daily (bid) tothe total daily dose of deutetrabenazine once daily for control ofabnormal involuntary movement, comprising:

-   -   a) administering to the human subject a last dose of the        deutetrabenazine twice daily (bid); and    -   b) the next day, administering to the human subject the total        daily dose of deutetrabenazine once daily (qd).

The deutetrabenazine once daily is, for example, a deutetrabenazineextended release osmotic dosage form disclosed herein.

Deutetrabenazine twice daily may refer to, for example, AUSTEDO® bidtablets or any equivalent thereof. As used herein, the term “last dose”refers to discontinuation of current treatment, for example,discontinuing treatment with deutetrabenazine twice daily. In specificembodiments, last dose of the deutetrabenazine twice daily may refer tothe second daily dose of deutetrabenazine twice daily, administered tothe human subject, for example, in the afternoon or evening.

In one embodiment, the human subject is being treated withdeutetrabenazine twice daily tablets at a total daily dose of 12 mg, andis transitioned to a total daily dose of 12 mg deutetrabenazine oncedaily.

In another embodiment, the human subject is being treated withdeutetrabenazine twice daily tablets at a total daily dose of 18 mg, andis transitioned to a total daily dose of 18 mg deutetrabenazine oncedaily.

In another embodiment, the human subject is being treated withdeutetrabenazine twice daily tablets at a total daily dose of 24 mg, andis transitioned to a total daily dose of 24 mg deutetrabenazine oncedaily.

In another embodiment, the human subject is being treateddeutetrabenazine twice daily tablets at a total daily dose of 30 mg, andis transitioned to a total daily dose of 30 mg deutetrabenazine oncedaily.

In another embodiment, the human subject is being treated withdeutetrabenazine twice daily tablets at a total daily dose of 36 mg, andis transitioned to a total daily dose of 36 mg deutetrabenazine oncedaily.

In another embodiment, the human subject is being treated withdeutetrabenazine twice daily tablets at a total daily dose of 42 mg, andis transitioned to a total daily dose of 42 mg deutetrabenazine oncedaily.

In another embodiment, the human subject is being treated withdeutetrabenazine twice daily tablets at a total daily dose of 48 mg, andis transitioned to a total daily dose of 48 mg deutetrabenazine oncedaily.

In one specific embodiment, the deutetrabenazine once daily is anextended-release osmotic dosage form, preferably, a deutetrabenazineosmotic dosage form according to any one of the embodiments of theinvention.

In yet another specific embodiment, the deutetrabenazine once dailyosmotic dosage form comprises:

-   -   a. a tablet core comprising an active layer and a push layer,        wherein the active layer comprises an amount of deutetrabenazine        microparticles and an active layer control release agent, and        wherein the push layer comprises an osmotic agent and a push        layer control release agent, and an optional tablet seal coat on        the outer surface of the tablet core, wherein about 70%-80% of        the total amount of deutetrabenazine microparticles present in        the dosage form is present within the active layer and wherein        about 20%-30% of the total amount of deutetrabenazine        microparticles present in the dosage form, is present within the        immediate release coating and wherein the deutetrabenazine        microparticles have a particle size with D₉₀ of 15 μm, a D₅₀ 10        μm, and/or a D₁₀ of 3 μm;    -   b. a semipermeable layer surrounding the tablet core;    -   c. a port extending through the semipermeable layer into the        tablet core; and    -   d. an optional immediate release coating external to the        semipermeable layer comprising a second amount of        deutetrabenazine microparticles.

In one embodiment, the deutetrabenazine once daily extended-releasedosage form is administered with food or without food.

In one embodiment, the abnormal involuntary movement being controlledduring the transition from the deutetrabenazine twice daily to thedeutetrabenazine once daily dose is chorea, akathisia, dyskinesia,tremor, tic, chorea associated with Huntington's disease, tardivedyskinesia, a tic associated with Tourette syndrome, Parkinson's diseaselevodopa-induced dyskinesia or dyskinesia in cerebral palsy. In oneembodiment, the abnormal involuntary movement being controlled is choreaassociated with Huntington's disease. In one embodiment, the abnormalinvoluntary movement being controlled is tardive dyskinesia.

Further provided is a method of transitioning a human subject beingtreated with a total daily dose of deutetrabenazine once daily todeutetrabenazine twice daily (bid) tablets at the same total daily dose,for control of abnormal involuntary movement, comprising:

-   -   a) administering a last dose of the deutetrabenazine once daily;        and    -   b) the next day, administering to the human subject the total        daily dose of deutetrabenazine twice daily.

As detailed above, a human subject is transitioned to the same totaldaily dose, for example, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg or 48mg.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 12 mg, and istransitioned to a total daily dose of 12 mg of deutetrabenazine twicedaily tablets.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 18 mg, and istransitioned to a total daily dose of 18 mg of deutetrabenazine twicedaily tablets.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 24 mg, and istransitioned to a total daily dose of 24 mg of deutetrabenazine twicedaily tablets.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 30 mg, and istransitioned to a total daily dose of 30 mg of deutetrabenazine twicedaily tablets.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 36 mg, and istransitioned to a total daily dose of 36 mg of deutetrabenazine twicedaily tablets.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 42 mg, and istransitioned to a total daily dose of 42 mg of deutetrabenazine twicedaily tablets.

In one embodiment, the human subject is being treated with a dose of adeutetrabenazine once daily at a total daily dose of 48 mg, and istransitioned to a total daily dose of 48 mg of deutetrabenazine twicedaily tablets.

In one specific embodiment, the deutetrabenazine once daily is anextended-release dosage form, preferably, an osmotic dosage formaccording to any one of the embodiments of the invention. In oneembodiment, the deutetrabenazine once daily extended-release dosage formis administered with food or without food.

In one embodiment, a human subject is treated with a deutetrabenazineonce daily osmotic dosage form and is transitioned to a deutetrabenazinetwice daily dosage form.

In one embodiment, the abnormal involuntary movement being controlledduring the transition from the once daily deutetrabenazine dosage formto the twice daily deutetrabenazine tablet is chorea, akathisia,dyskinesia, tremor, tic, chorea associated with Huntington's disease,tardive dyskinesia, a tic associated with Tourette syndrome, Parkinson'sdisease levodopa-induced dyskinesia or dyskinesia in cerebral palsy. Inone embodiment, the abnormal involuntary movement being controlled ischorea associated with Huntington's disease. In one embodiment, theabnormal involuntary movement being controlled is tardive dyskinesia.

Further provided is a method of transitioning a human subject beingtreating with a daily amount of tetrabenazine to a once daily amount ofdeutetrabenazine, for control of abnormal involuntary movement from,comprising:

-   -   a) administering the last dose of tetrabenazine; and    -   b) the next day, administering to the human subject a once daily        deutetrabenazine osmotic dosage form wherein:        -   the daily amount of tetrabenazine is 12.5 mg and the once            daily amount of deutetrabenazine is 6 mg; or        -   wherein the daily amount of tetrabenazine is 25 mg and the            once daily amount of deutetrabenazine is 12 mg; or        -   wherein the daily amount of tetrabenazine is 37.5 mg and the            once daily amount of deutetrabenazine is 18 mg; or        -   wherein the daily amount of tetrabenazine is 50 mg and the            once daily amount of deutetrabenazine is 24 mg; or        -   wherein the daily amount of tetrabenazine is 62.5 mg and the            once daily amount of deutetrabenazine is 30 mg; or        -   wherein the daily amount of tetrabenazine is 75 mg and the            once daily amount of deutetrabenazine is 36 mg; or        -   wherein the daily amount of tetrabenazine is 87.5 mg and the            once daily amount of deutetrabenazine is 42 mg; or        -   wherein the daily amount of tetrabenazine is 100 mg and the            once daily amount of deutetrabenazine is 48 mg.

In some embodiments, the daily amount of tetrabenazine is administeredin divided doses, for example, in two, three, or more divided doses.

In one embodiment, the abnormal involuntary movement being controlledduring the transition from tetrabenazine to once-daily dose ofdeutetrabenazine is chorea, akathisia, dyskinesia, tremor, tic, choreaassociated with Huntington's disease, tardive dyskinesia, a ticassociated with Tourette syndrome, Parkinson's disease levodopa-induceddyskinesia or dyskinesia in cerebral palsy. In one embodiment, theabnormal involuntary movement being controlled is chorea associated withHuntington's disease. In one embodiment, the abnormal involuntarymovement being controlled is tardive dyskinesia.

In one embodiment, the once daily deutetrabenazine extended-releasedosage form is administered with food or without food.

The present disclosure provides oral dosage forms and methods, accordingto any of the following aspects:

Aspects

-   1. An osmotic dosage form for once daily administration to a subject    in need thereof comprising:    -   a. a tablet core comprising an active layer comprising an amount        of deutetrabenazine microparticles and a push layer;    -   b. a semipermeable layer surrounding the tablet core; and    -   c. a port extending from the periphery of the dosage form into        the tablet core.-   2. The dosage form of Aspect 1, wherein the active layer further    comprises an active layer control release agent.-   3. The dosage form of Aspect 2, wherein the active layer control    release agent comprises a polymer having a viscosity of about 50-150    mPa s or about 55-90 mPa s.-   4. The dosage form of Aspect 2 or Aspect 3, wherein the active layer    control release agent comprises at least one of a polyoxyethylene    polymer, an ionic hydrogel, a hydrophilic polymer, a hydrophobic    polymer or any mixture thereof-   5. The dosage form of Aspect 4, wherein the active layer control    release agent comprises a polyoxyethylene polymer that is    polyethylene oxide.-   6. The dosage form of Aspect 5, wherein the polyethylene oxide    within the active layer has an average molecular weight of 100,000    daltons to 500,000 daltons.-   7. The dosage form of Aspect 6, wherein the polyethylene oxide    within the active layer has an average molecular weight of 200,000    daltons.-   8. The dosage form of any one of Aspects 2-7, wherein the active    layer control release agent is present in the active layer in an    amount of about 60% to about 98% by weight, based on the total    weight of the active layer.-   9. The dosage form of Aspect 8, wherein the active layer control    release agent is present in the active layer in an amount of about    70% to about 95% by weight, based on the total weight of the active    layer, or about 80% to about 90%, or about 85% to about 95%, by    weight, based on the total weight of the active layer.-   10. The dosage form of any one of Aspects 2-9, wherein the weight    ratio of the amount of deutetrabenazine microparticles and the    active layer control release agent in the active layer is 2:3-1:50    or 2:5-1:5 or 1:4-1:9 or 1:5-1:19 or 1:5-1:7 or 1:12-1:15 or    1:20-1:30.-   11. The dosage form of any preceding Aspect, wherein the active    layer further comprises at least one active layer antioxidant.-   12. The dosage form of Aspect 11, wherein the active layer    antioxidant comprises at least one of tertiary butyl-4-methoxyphenol    (mixture of 2 and 3-isomers), 2,6-ditertiary butyl-p-cresol, propyl    gallate, 6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin),    nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole,    butylated hydroxytoluene or any mixture thereof-   13. The dosage form of Aspect 12, wherein the active layer    antioxidant comprises a mixture of butylated hydroxyanisole and    butylated hydroxytoluene.-   14. The dosage form of any one of Aspects 11-13, wherein the active    layer antioxidant is present in the active layer in an amount of    about 0.001% to about 1% by weight, based on the total weight of the    active layer.-   15. The dosage form of any preceding Aspect, wherein the active    layer further comprises at least one of active layer binder.-   16. The dosage form of Aspect 15, wherein the active layer binder    comprises at least one of hypromellose (hydroxypropyl    methylcellulose), starch, gelatin, agar, natural or synthetic gums    or any mixture thereof-   17. The dosage form of Aspect 16, wherein the active layer binder    comprises hypromellose.-   18. The dosage form of any one of Aspects 15-17, wherein the active    layer binder is present in the active layer in an amount of about 2%    to about 20% by weight, based on the total weight of the active    layer.-   19. The dosage form of any preceding Aspect, wherein the active    layer further comprises one or more pharmaceutically acceptable    excipients.-   20. The dosage form of any preceding Aspect, wherein the active    layer comprises deutetrabenazine microparticles, and an active layer    control release agent which is a polymer having a viscosity of about    55-90 mPa s and an antioxidant.-   21. The dosage form of Aspect 20, wherein the active layer comprises    deutetrabenazine microparticles, butylated hydroxyanisole, butylated    hydroxytoluene, polyethylene oxide, hypromellose and magnesium    stearate.-   22. The dosage form of any preceding Aspect, wherein the push layer    comprises an osmotic agent and a push layer control release agent.-   23. The dosage form of Aspect 22, wherein the osmotic agent    comprises an inorganic salt, a carbohydrate or any mixture thereof-   24. The dosage form of Aspect 23, wherein the osmotic agent    comprises a carbohydrate that is d-mannitol, sorbitol, inositol, a    monosaccharide, an oligosaccharide, a polysaccharide, or any mixture    thereof-   25. The dosage form of Aspect 23, wherein the osmotic agent    comprises an inorganic salt that is magnesium sulfate, magnesium    chloride, potassium sulfate, sodium chloride, sodium sulfate,    lithium sulfate, sodium phosphate, potassium phosphate, or any    mixture thereof-   26. The dosage form of Aspect 25, wherein the osmotic agent is    /comprises? sodium chloride.-   27. The dosage form of any one of Aspects 22-26, wherein the osmotic    agent is present in the dosage form in an amount of about 5% to    about 50% by weight, based on the total weight of the dosage form.-   28. The dosage form of Aspect 27, wherein the osmotic agent is    present in the dosage form in an amount of about 5% to about 20% by    weight, based on the total weight of the dosage form.-   29. The dosage form of Aspect 27 or Aspect 28, wherein the osmotic    agent is present in the dosage form in an amount of about 8% to    about 10% by weight, based on the total weight of the dosage form.-   30. The dosage form of any one of Aspects 27-29, wherein the osmotic    agent is present in the push layer in an amount of about 20% to    about 40% by weight, based on the total weight of the push layer.-   31. The dosage form of Aspect 30, wherein the osmotic agent is    present in the push layer in an amount of about 30% by weight, based    on the total weight of the push layer.-   32. The dosage form of any one of Aspects 22-31, wherein the push    layer control release agent comprises a polymer having a viscosity    of about 5500-7500 mPa s.-   33. The dosage form of Aspect 32, wherein the polymer having a    viscosity of about 5500-7500 mPa s is selected from a    polyoxyethylene polymer, an ionic hydrogel, a hydrophilic polymer, a    hydrophobic polymer or any mixture thereof-   34. The dosage form of Aspect 33, wherein the push layer control    release agent is a polyethylene oxide.-   35. The dosage form of Aspect 34, wherein the polyethylene oxide    within the push layer has an average molecular weight of 1,000,000    daltons to 7,000,000 daltons.-   36. The dosage form of Aspect 35 wherein the polyethylene oxide    within the push layer has an average molecular weight of 5,000,000    daltons.-   37. The dosage form of any one of Aspect 32-36, wherein the push    layer control release agent is present in the push layer in an    amount of about 50% to about 80% by weight, based on the total    weight of the push layer.-   38. The dosage form of Aspect 37, wherein the push layer control    release agent is present in the push layer in an amount of about 60%    to about 70% by weight, based on the total weight of the push layer.-   39. The dosage form of any one of Aspects 22-38, wherein the weight    ratio of the osmotic agent and the push layer control release agent    in the push layer is 1:2-1:3.5 or 1:2-1:2.5.-   40. The dosage form of any one of Aspects 22-39, wherein the push    layer further comprises a push layer binder.-   41. The dosage form of Aspect 40, wherein the push layer binder    comprises hypromellose (hydroxypropyl methylcellulose), starch,    gelatin, agar, natural or synthetic gums, or any mixture thereof-   42. The dosage form of Aspect 41, wherein the push layer binder    comprises hypromellose.-   43. The dosage form of any one of Aspects 40-42, wherein the push    layer binder is present in the push layer in an amount of about 2%    to about 10% by weight, based on the total weight of the push layer.-   44. The dosage form of Aspect 43, wherein the push layer binder is    present in the push layer in an amount of about 4% to about 6% by    weight, based on the total weight of the push layer or about 3% to    about 6% by weight, based on the total weight of the push layer.-   45. The dosage form of any one of Aspects 22-44, wherein the push    layer further comprises a pharmaceutically acceptable excipient.-   46. The dosage form of any one of Aspects 22-45, wherein the push    layer comprises sodium chloride and a polymer having a viscosity of    about 5500-7500 mPa s.-   47. The dosage form of Aspect 46, wherein the push layer comprises    sodium chloride, polyethylene oxide, hydroxypropyl methylcellulose,    a colorant, and magnesium stearate.-   48. The dosage form of any preceding Aspect, wherein the    semipermeable layer comprises a water soluble polymer, a water    insoluble polymer or any mixture thereof-   49. The dosage form of Aspect 48, wherein the semipermeable layer    comprises a water insoluble polymer selected from cellulose acetate,    cellulose diacetate, cellulose triacetate, cellulose propionate,    cellulose acetate butyrate, cellulose ethers like ethyl cellulose,    agar acetate, amylose triacetate, betaglucan acetate, poly(vinyl    methyl) ether copolymers, poly(orthoesters), poly acetals and    selectively permeable poly(glycolic acid), poly(lactic acid)    derivatives, Eudragit cellulose acetate or any mixture thereof-   50. The dosage form of Aspect 49, wherein the water insoluble    polymer is cellulose acetate, comprising 32%-39.8% acetyl content.-   51. The dosage form of any preceding Aspect, wherein the    semipermeable layer comprises cellulose acetate and polyethylene    glycol.-   52. The dosage form of any one of Aspects 48-51, wherein the water    insoluble polymer is present in the semipermeable layer in an amount    of about 80% to about 99.9% by weight, based on the weight of the    semipermeable layer or about 85% to about 95% by weight, based on    the weight of the semipermeable layer.-   53. The dosage form of any preceding Aspect, wherein the    semipermeable layer comprises a pore-forming agent.-   54. The dosage form of Aspect 53, wherein the pore-forming comprises    a water soluble sugar, a water soluble salt, a water soluble    solvent, a water soluble polymer or any mixture thereof-   55. The dosage form of Aspect 54, wherein the pore-forming agent is    a water soluble solvent which is polyethylene glycol.-   56. The dosage form of any one of Aspects 53-55, wherein the    pore-forming agent is present in the semipermeable layer in an    amount of about 0.1% to about 20% by weight of the semipermeable    layer.-   57. The dosage form of Aspect m 56, wherein the pore-forming agent    is present in the semipermeable layer in an amount of about 8% to    about 15% by weight of the semipermeable layer.-   58. The dosage form of any preceding Aspect, wherein the weight    ratio of the semipermeable layer and the tablet core is 1:8-1:10.-   59. The dosage form of any preceding Aspect, wherein the port has a    diameter of from about 0.1 mm to about 1 mm.-   60. The dosage form of Aspect 59, wherein the port has a diameter of    from about 0.4 mm to about 0.8 mm.-   61. The dosage form of any preceding Aspect, further comprising a    tablet core seal coat on the outer surface of the tablet core.-   62. The dosage form of any preceding Aspect, further comprising a    semipermeable layer seal coat on the outer surface of the    semipermeable layer.-   63. The dosage form of any one of Aspect 61-62, wherein the tablet    core seal coat and or the semipermeable layer seal coat comprises a    binder.-   64. The dosage form of Aspect 63, wherein the tablet core seal coat    binder and or the semipermeable layer seal coat binder comprise:    hypromellose (hydroxypropyl methylcellulose), starch, gelatin, agar,    natural gums, synthetic gums and any mixture thereof-   65. The dosage form of Aspect 64, wherein the tablet core seal coat    binder and or the semipermeable layer seal coat binder is    hypromellose.-   66. The dosage form of any one of Aspects 63-65, wherein the total    amount of the binder within the dosage form is about 0 to about 20%    by weight, based on the total weight of the dosage form; 5% to about    15% by weight, based on the total weight of the dosage form; or 5%    to about 20% by weight, based on the total weight of the dosage    form.-   67. The dosage form of Aspect 66, wherein the total amount of the    binder within the dosage form is about 8% to about 10% by weight,    based on the total weight of the dosage form or about 10% to about    20% by weight, based on the total weight of the dosage form, or    about 10% to about 20% by weight, based on the total weight of the    dosage form.-   68. The dosage form of any preceding Aspect, further comprising an    immediate release coating external to the semipermeable membrane,    the immediate release coating comprising a second amount of    deutetrabenazine microparticles.-   69. The dosage form of Aspect 68, wherein the immediate release    coating comprises about 0.1% to about 25% by weight deutetrabenazine    microparticles, based on the total weight of the dosage form or    about 0.2% to about 5% by weight deutetrabenazine microparticles,    based on the total weight of the dosage form or about 0.3% to about    2% by weight deutetrabenazine microparticles, based on the total    weight of the dosage form.-   70. The dosage form of Aspect 69, wherein the dosage form comprises    a total of 24 mg of deutetrabenazine microparticles and the    immediate release coating comprises about 1% to about 2% by weight    deutetrabenazine microparticles, based on the total weight of the    dosage form or wherein the dosage form comprises a total of 12 mg of    deutetrabenazine microparticles and the immediate release coating    comprises about 0.5% to about 1% by weight deutetrabenazine    microparticles, based on the total weight of the dosage form or    wherein the dosage form comprises a total of 6 mg of    deutetrabenazine microparticles and the immediate release coating    comprises about 0.1% to about 0.5% by weight deutetrabenazine    microparticles, based on the total weight of the dosage form.-   71. The dosage form of any preceding Aspect, wherein about 70% to    99% of the total amount of deutetrabenazine microparticles in the    dosage form, is within the active layer.-   72. The dosage form of any preceding Aspect, wherein about 5% to 30%    of the total amount of deutetrabenazine microparticles in the dosage    form, is within immediate release coating.-   73. The dosage form of any preceding Aspect, wherein about 70%-80%    of the total amount of deutetrabenazine microparticles in the dosage    form, is within the active layer and wherein about 20%-30% of the    total amount of deutetrabenazine microparticles in the dosage form,    is within immediate release coating.-   74. The dosage form of any one of Aspects 68-73, wherein the    immediate release coating further comprises an immediate release    coating antioxidant.-   75. The dosage form of Aspect 74, wherein the immediate release    coating antioxidant comprises: tertiary butyl-4-methoxyphenol    (mixture of 2 and 3-isomers), 2,6-ditertiary butyl-p-cresol, propyl    gallate, 6-ethoxy-1,2-digydro-2,2,4-trimethylquinoline (ethoxyquin),    nordihydroguaiaretic acid (NDGA), butylated hydroxyanisole,    butylated hydroxytoluene and any mixture thereof-   76. The dosage form of Aspect 75, wherein the immediate release    coating comprises a mixture of butylated hydroxyanisole, and    butylated hydroxytoluene.-   77. The dosage form of any one of Aspects 68-76, wherein the    immediate release coating further comprises an additional    pharmaceutically acceptable excipient.-   78. The dosage form of any one of Aspects 68-77, wherein the    immediate release coating comprises: deutetrabenazine    microparticles, butylated hydroxyanisole, butylated hydroxytoluene,    hypromellose and polysorbate 80.-   79. The dosage form of any preceding Aspect, wherein the total    amount of deutetrabenazine microparticles in the dosage form is from    about 6 mg to about 48 mg.-   80. The dosage form of any preceding Aspect, wherein the total    amount of deutetrabenazine microparticles in the dosage form is    about 6 mg.-   81. The dosage form of any preceding Aspect, wherein the total    amount of deutetrabenazine microparticles in the dosage form is    about 12 mg.-   82. The dosage form of any preceding Aspect, wherein the total    amount of deutetrabenazine microparticles in the dosage form is    about 24 mg.-   83. The dosage form of any preceding Aspect, wherein the total    amount of deutetrabenazine microparticles in the dosage form is    about 48 mg.-   84. The dosage form of any preceding Aspect, wherein the total    amount of deutetrabenazine microparticles is about 0.5% to about 15%    by weight, based on the total weight of the dosage form.-   85. The dosage form of Aspect 84, wherein the total amount of    deutetrabenazine microparticles is about 1% to about 10% by weight,    based on the total weight of the dosage form.-   86. The dosage form of Aspect 85, comprising a total of 6 mg of    deutetrabenazine microparticles, wherein the total amount of    deutetrabenazine microparticles is about 0.5% to about 3% by weight,    based on the total weight of the dosage form or a dosage form    comprising a total of 12 mg of deutetrabenazine microparticles,    wherein the total amount of deutetrabenazine microparticles is about    1% to about 5% by weight, based on the total weight of the dosage    form or a dosage form comprising a total of 24 mg of    deutetrabenazine microparticles, wherein the total amount of    deutetrabenazine microparticles is about 5% to about 10% by weight,    based on the total weight of the dosage form.-   87. The dosage form of any preceding Aspect, wherein the    deutetrabenazine microparticles have a particle size of about 1 μm    to about 30 μm in diameter.-   88. The dosage form of Aspect 87, wherein the deutetrabenazine    microparticles have a particle size providing a D₉₀ of 15 μm.-   89. The dosage form of Aspect 87 or Aspect 88, wherein the    deutetrabenazine microparticles have a particle size providing a D₅₀    10 μm.-   90. The dosage form of any one of Aspects 87-89, wherein the    deutetrabenazine microparticles have a particle size providing a D₁₀    of 3 μm.-   91. A method of treating a hyperkinetic movement disorder in a    subject in need thereof comprising orally administering, on a once    daily basis to the subject, an osmotic dosage form according to any    one of the preceding Aspects.-   92. The method of Aspect 91, wherein the movement disorder is    selected from chorea, akathisia, dyskinesia, tremor, and tic.-   93. The method of Aspect 92, wherein the movement disorder is    selected from chorea associated with Huntington's disease, tardive    dyskinesia, a tic associated with Tourette syndrome, Parkinson's    disease levodopa-induced dyskinesia and dyskinesia in cerebral    palsy.-   94. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 6 mg of deutetrabenazine microparticles provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean AUC_(0-inf) of about 91,250 to 142,750    h*pg/mL.-   95. The method of any one of Aspects 91-94, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 6 mg of deutetrabenazine microparticles provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean C_(max) of less than about 4,600 pg/mL.-   96. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 12 mg of deutetrabenazine microparticles, provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean AUC_(0-inf) of about 182,500 to 285,500    h*pg/mL.-   97. The method of any one of Aspects 91-93 or 96, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 12 mg of deutetrabenazine microparticles, provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean C_(max) of less than about 9,200 pg/mL.-   98. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 24 mg of deutetrabenazine microparticles, provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean AUC_(0-inf) of about 365,000 to 571,000    h*pg/mL.-   99. The method of any one of Aspects 91-93 or Aspect 98 comprising    orally administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 24 mg of deutetrabenazine microparticles, provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean C_(max) of less than about 18,400 pg/mL.-   100. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 36 mg of deutetrabenazine microparticles, provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean AUC_(0-inf) of about 547,500 to 856,500    h*pg/mL.-   101. The method of any one of Aspects 91-93 or Aspect 100,    comprising orally administering to the subject a once daily osmotic    dosage form according to any one of Aspects 1-90, wherein single    dose administration of the osmotic dosage form, which comprises a    total amount of 36 mg of deutetrabenazine microparticles, provides    an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine    that includes a geometric mean C_(max) of less than about 27,600    pg/mL.-   102. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90, wherein single dose    administration of the osmotic dosage form, which comprises a total    amount of 48 mg of deutetrabenazine microparticles, provides an in    vivo plasma profile for total α- and β-dihydrodeutetrabenazine that    includes a geometric mean AUC_(0-inf) of about 730,000 to 1,142,000    h*pg/mL.-   103. The method of any one of Aspects 91-93 or Aspect 102,    comprising orally administering to the subject a once daily osmotic    dosage form according to any one of Aspects 1-90, wherein single    dose administration of the osmotic dosage form, which comprises a    total amount of 48 mg of deutetrabenazine microparticles, provides    an in vivo plasma profile for total α- and β-dihydrodeutetrabenazine    that includes a geometric mean C_(max) of less than about 36,800    pg/mL.-   104. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90 wherein the osmotic dosage form    which comprises a total amount of 6 mg of deutetrabenazine    microparticles, provides an in vivo plasma profile for total α- and    β-dihydrodeutetrabenazine at steady state that includes a mean    AUC₀₋₂₄ of about 102,500 to 200,000 h*pg/mL.-   105. The method of any one of Aspects 91-93 or Aspect 104,    comprising orally administering to the subject a once daily osmotic    dosage form according to any one of Aspects 1-90 wherein the osmotic    dosage form which comprises a total amount of 6 mg of    deutetrabenazine microparticles, provides an in vivo plasma profile    for total α- and β-dihydrodeutetrabenazine at steady state that    includes a mean C_(max) of less than about 10,000 pg/mL.-   106. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90 wherein the osmotic dosage form    which comprises a total amount of 12 mg of deutetrabenazine    microparticles provides an in vivo plasma profile for total α- and    β-dihydrodeutetrabenazine at steady state that includes a mean    AUC₀₋₂₄ of about 205,000 to 400,000 h*pg/mL.-   107. The method of any one of Aspects 91-93 or Aspect 106,    comprising orally administering to the subject a once daily osmotic    dosage form according to any one of Aspects 1-90 wherein the osmotic    dosage form which comprises a total amount of 12 mg of    deutetrabenazine microparticles provides an in vivo plasma profile    for total α- and β-dihydrodeutetrabenazine at steady state that    includes a mean C_(max) of less than about 20,000 pg/mL.-   108. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90 wherein the osmotic dosage form    which comprises a total amount of 24 mg of deutetrabenazine    microparticles, provides an in vivo plasma profile for total α- and    β-dihydrodeutetrabenazine at steady state that includes a mean    AUC₀₋₂₄ of about 410,000 to 800,000 h*pg/mL.-   109. The method of any one of Aspects 91-93 or Aspect 108 comprising    orally administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90 wherein the osmotic dosage form    which comprises a total amount of 24 mg of deutetrabenazine    microparticles, provides an in vivo plasma profile for total α- and    β-dihydrodeutetrabenazine at steady state that includes a mean    C_(max) of less than about 40,000 pg/mL.-   110. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90 wherein the osmotic dosage form    which comprises a total amount of 36 mg of deutetrabenazine    microparticles, provides an in vivo plasma profile for total α- and    β-dihydrodeutetrabenazine at steady state that includes a mean    AUC₀₋₂₄ of about 615,000 to 1,200,000 h*pg/mL.-   111. The method of any one of Aspects 91-93 or Aspect 110,    comprising orally administering to the subject a once daily osmotic    dosage form according to any one of Aspects 1-90 wherein the osmotic    dosage form which comprises a total amount of 36 mg of    deutetrabenazine microparticles, provides an in vivo plasma profile    for total α- and β-dihydrodeutetrabenazine at steady state that    includes a mean C_(max) of less than about 60,000 pg/mL.-   112. The method of any one of Aspects 91-93, comprising orally    administering to the subject a once daily osmotic dosage form    according to any one of Aspects 1-90 wherein the osmotic dosage form    which comprises a total amount of 48 mg of deutetrabenazine    microparticles, provides an in vivo plasma profile for total α- and    β-dihydrodeutetrabenazine at steady state that includes a mean    AUC₀₋₂₄ of about 820,000 to 1,600,000 h*pg/mL.-   113. The method of any one of Aspects 91-93 or Aspect 112,    comprising orally administering to the subject a once daily osmotic    dosage form according to any one of Aspects 1-90 wherein the osmotic    dosage form which comprises a total amount of 48 mg of    deutetrabenazine microparticles, provides an in vivo plasma profile    for total α- and β-dihydrodeutetrabenazine at steady state that    includes a mean C_(max) of less than about 80,000 pg/mL.-   114. The method of any one of Aspects 91-113, comprising    administering an osmotic dosage form according to any one of Aspects    1-90, wherein not more than 15% of the drug formulation is released    after 2 hours when tested in 500 mL acid phosphate buffer at pH 3.0    using a USP II dissolution apparatus.-   115. The method of any one of Aspects 91-113, comprising    administering an osmotic dosage form according to any one of Aspects    1-90, wherein not more than 60% of the drug formulation is released    after 8 hours when tested in 500 mL acid phosphate buffer at pH 3.0    using a USP II dissolution apparatus.-   116. The dosage form or method of any preceding Aspect, wherein the    dosage form is administered with food.-   117. The dosage form or method of any one of Aspects 1-115, wherein    the dosage form is administered under fasting conditions.

All patents, patent applications, and publications are hereinincorporated by reference to the same extent as if each individualpublication was specifically and individually indicated to beincorporated by reference. The invention illustratively described hereinmay be practiced in the absence of any element(s) not specificallydisclosed herein. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

For the foregoing embodiments, each embodiment disclosed herein iscontemplated as being applicable to each of the other disclosedembodiments. For instance, the elements recited in the methodembodiments can be used in the pharmaceutical composition, package, anduse/method embodiments described herein and vice versa.

EXAMPLES

The following examples are provided to supplement the prior disclosureand to provide a better understanding of the subject matter describedherein. These examples should not be considered to limit the describedsubject matter. It is understood that the examples and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be apparent to personsskilled in the art and are to be included within, and can be madewithout departing from, the true scope of the disclosure.

Example 1— Manufacturing Process for Osmotic Tablets, 24 mgDeutetrabenazine

FIG. 2a and FIG. 2b provide flowcharts of the general manufacturingprocesses for osmotic dosage forms according to the present disclosure.Tables 1-13, below, provide non-limiting examples of the materials andtheir relative amounts used to produce the dosage forms describedherein. The preparation method was as follows:

A: Active layer materials processing: deutetrabenazine (micronized) andthe active layer control release agent were passed through a #30 meshscreen and combined with a binder (previously passed through a #20 meshscreen). The mixture was introduced into a high shear granulator and drymixed for about 5 minutes. While mixing, antioxidant (pre dissolved inalcohol) was added to the mixing powders to granulate the material.Additional mixing continued until the desired granulation end-point wasachieved. The resulting granulation is wet screened to break up anyoversized agglomerates. The material was fed into a diffusive mixer(V-Blender) where it was blended for about 15 minutes. Lubricant thathad been passed through a #30 mesh screen was added to the blendedmaterial in the V-Blender. The contents were lubricated for about 5minutes.

B: Tablet core compression: the active layer materials were dischargedinto a bilayer rotary tablet press. The push layer materials (osmoticagent, push layer control release agent and optionally a binder, acolorant and a lubricant) were combined and further fed into the bilayerrotary tablet press. The tablet core was compressed.

C: Optional tablet core seal coat: A tablet core seal coat comprising abinder solution was applied on the tablet core.

D: Semipermeable layer: Semipermeable layer comprising a solution ofcellulose acetate and an optional pore-forming agent was applied to thetablet core, or sealed tablet core, using a pan coater.

E: Optional Semipermeable layer seal coat: Semipermeable layer seal coatcomprising a binder solution was applied on the tablet compromising thesemipermeable wall.

F: Creating an exit means: a pore was laser-drilled through the layersinto the active layer.

A final immediate release coating comprising deutetrabenazine isoptionally applied, using similar materials and following the processingsteps as detailed above for active layer.

TABLE 1 Component Amount (mg) Deutetrabenazine (micronized) 24.00Polyethylene Oxide, NF (Polyox ® WSR N80) 123 Polyethylene Oxide, NF(FP) (Polyox ® WSR 56.23 Coagulant, Fine Powder) Hypromellose 2910 8.6Magnesium Stearate 0.87 Sodium Chloride, USP (Powder) 21.91Hydroxypropyl Cellulose NF (Klucel ® EXF) 3.16 FD&C Red No. 40 AluminumLake HT 38%-42% 0.23 Cellulose Acetate, NF 398-10 11.87 CelluloseAcetate, NF 320S 0.62 Polyethylene Glycol 3350 0.62 Purified Water, USPn.a. Acetone n.a. Total 251.11

TABLE 2 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Polyethylene Oxide, NF (Polyox ® WSR N80) 123 Polyethylene Oxide, NF(FP) (Polyox ® WSR 56.23 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 8.6 Magnesium Stearate 0.87 Sodium Chloride,USP (Powder) 21.91 Hydroxypropyl Cellulose NF (Klucel ® EXF) 3.16 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.23 Cellulose Acetate, NF 398-1018.09 Cellulose Acetate, NF 320S 0.95 Polyethylene Glycol 3350 1.9Purified Water, USP n.a. Acetone n.a. Total 260.34

TABLE 3 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Polyethylene Oxide, NF (Polyox ® WSR N80) 123 Polyethylene Oxide, NF(FP) (Polyox ® WSR 71.73 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 16.1 Magnesium Stearate 1 Sodium Chloride, USP(Powder) 27.94 Hydroxypropyl Cellulose NF (Klucel ® EXF) 4.03 FD&C RedNo. 40 Aluminum Lake HT 38%-42% 0.3 Cellulose Acetate, NF 398-10 21.38Cellulose Acetate, NF 320S 2.37 Polyethylene Glycol 3350 2.77 PurifiedWater, USP n.a. Acetone n.a. Total 296

TABLE 4 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Polyethylene Oxide, NF (Polyox ® WSR N80) 123 Polyethylene Oxide, NF(FP) (Polyox ® WSR 80.23 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 16.92 Magnesium Stearate 1.07 Sodium Chloride,USP (Powder) 48.86 Hydroxypropyl Cellulose NF (Klucel ® EXF) 4.51 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.33 Cellulose Acetate, NF 398-1023.82 Cellulose Acetate, NF 320S 2.64 Polyethylene Glycol 3350 3.08Purified Water, USP n.a. Acetone n.a. Total 329.87

TABLE 5 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Polyethylene Oxide, NF (Polyox ® WSR N80) 123 Polyethylene Oxide, NF(FP) (Polyox ® WSR 82.29 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 22.15 Magnesium Stearate 1.09 Sodium Chloride,USP (Powder) 49.66 Hydroxypropyl Cellulose NF (Klucel ® EXF) 4.63 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.34 Cellulose Acetate, NF 398-1024.47 Cellulose Acetate, NF 320S 2.72 Polyethylene Glycol 3350 3.17Purified Water, USP n.a. Acetone n.a. Total 338.92

TABLE 6 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Simethicone 30% Emulsion, USP 2 Lactose Monohydrate 41 Sodium LaurylSulfate, NF 12.7 Sodium Bicarbonate 1 Polyethylene Oxide, NF (Polyox ®WSR N80) 123 Polyethylene Oxide, NF (FP) (Polyox ® WSR 101.5 Coagulant,Fine Powder) Methocel ® E5 Premium (Hypromellose 2910, USP) 19.67Magnesium Stearate 1.4 Sodium Chloride, USP (Powder) 39.5 HydroxypropylCellulose NF (Klucel ® EXF) 11.7 FD&C Red No. 40 Aluminum Lake HT38%-42% 0.4 Cellulose Acetate, NF 398-10 41 Cellulose Acetate, NF 320S4.56 Polyethylene Glycol 3350 4.56 Purified Water, USP n.a. Acetone n.a.Total 429.39

TABLE 7 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Simethicone 30% Emulsion, USP 2 Lactose Monohydrate 41 Sodium LaurylSulfate, NF 12.7 Edetate Disodium Dihydrate 10 Sodium Bicarbonate 1Polyethylene Oxide, NF (Polyox ® WSR N80) 123 Polyethylene Oxide, NF(FP) (Polyox ® WSR 71.7 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 18.65 Magnesium Stearate 1.2 Sodium Chloride,USP (Powder) 27.9 Hydroxypropyl Cellulose NF (Klucel ® EXF) 10 FD&C RedNo. 40 Aluminum Lake HT 38%-42% 0.3 Cellulose Acetate, NF 398-10 43.46Cellulose Acetate, NF 320S 4.83 Polyethylene Glycol 3350 4.83 PurifiedWater, USP n.a. Acetone n.a. Total 398

TABLE 8 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Simethicone 30% Emulsion, USP 2 Lactose Monohydrate 41 Sodium LaurylSulfate, NF 12.7 Edetate Disodium Dihydrate 5 Ascorbic acid 5 SodiumBicarbonate 1 Polyethylene Oxide, NF (Polyox ® WSR N80) 123 PolyethyleneOxide, NF (FP) (Polyox ® WSR 71.7 Coagulant, Fine Powder) Methocel ® E5Premium (Hypromellose 2910, USP) 18.65 Magnesium Stearate 1.2 SodiumChloride, USP (Powder) 27.9 Hydroxypropyl Cellulose NF (Klucel ® EXF) 10FD&C Red No. 40 Aluminum Lake HT 38%-42% 0.3 Cellulose Acetate, NF398-10 43.46 Cellulose Acetate, NF 320S 4.83 Polyethylene Glycol 33504.83 Purified Water, USP n.a. Acetone n.a. Total 398

TABLE 9 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1.00 Butylated Hydroxytoluene, NF 0.40Polyethylene Oxide, NF (Polyox ® WSR N80) 123.00 Polyethylene Oxide, NF(FP) (Polyox ® WSR 68.62 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 30.23 Sodium Chloride, USP (Powder) 30.23 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.32 Magnesium Stearate, NF 0.71Cellulose Acetate, NF (398-10) 23.8 Cellulose Acetate, NF (CA 320S) 2.66Polyethylene Glycol 3350, NF 2.66 Hydroxypropyl Cellulose (Klucel ® LF)9.2 Polysorbate 80 NF 4 Opadry ® II Gray 85F97586 9.6 Purified Water,USP n.a. Acetone n.a. Alcohol, USP (Ethyl Alcohol 190 proof) n.a. Total330.4

TABLE 10 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 1 Butylated Hydroxytoluene, NF 0.4Polyethylene Oxide, NF (Polyox WSR N80) 123.00 Polyethylene Oxide, NF(FP) (Polyox WSR 71.7 Coagulant, Fine Powder) Methocel E5 Premium(Hypromellose 2910, USP) 25.13 Sodium Chloride, USP (Powder) 27.9 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.3 Magnesium Stearate, NF 1Cellulose Acetate, NF (398-10) 23.83 Cellulose Acetate, NF (CA 320S)2.66 Polyethylene Glycol 3350, NF 2.66 Hydroxypropyl Cellulose (KlucelLF) 8.83 Polysorbate 80 NF 4 Purified Water, USP n.a. Acetone n.a. Total316.4

TABLE 11 Component Amount (mg) Deutetrabenazine (micronized) 24.00Butylated Hydroxyanisole, NF 0.5 Butylated Hydroxytoluene, NF 0.36Polyethylene Oxide, NF (Polyox WSR N80) 123.4 Polyethylene Oxide, NF(FP) (Polyox WSR 68.63 Coagulant, Fine Powder) Methocel E5 Premium(Hypromellose 2910, USP) 41.86 Sodium Chloride, USP (Powder) 30.22 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.32 Magnesium Stearate, NF 0.7Cellulose Acetate, NF (398-10) 27.03 Cellulose Acetate, NF (CA 320S)3.02 Polyethylene Glycol 3350, NF 3.02 Hydroxypropyl Cellulose (KlucelLF) 9.2 Opadry ® II Gray 85F97586 9.97 Purified Water, USP n.a. Acetonen.a. Total 342.2

TABLE 12 Component Amount (mg) Deutetrabenazine (micronized) 12.00Butylated Hydroxyanisole, NF 1.00 Butylated Hydroxytoluene, NF 0.40Polyethylene Oxide, NF (Polyox ® WSR N80) 132.6 Polyethylene Oxide, NF(FP) (Polyox ® WSR 68.63 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 30.25 Sodium Chloride, USP (Powder) 30.22 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.32 Magnesium Stearate, NF 0.72Cellulose Acetate, NF (398-10) 23.8 Cellulose Acetate, NF (CA 320S) 2.66Polyethylene Glycol 3350, NF 2.66 Hydroxypropyl Cellulose (Klucel ® LF)9.2 Polysorbate 80 NF 4 Opadry ® II Gray 85F97586 9.6 Purified Water,USP n.a. Acetone n.a. Alcohol, USP (Ethyl Alcohol 190 proof) n.a. Total328

TABLE 13 Component Amount (mg) Deutetrabenazine 12.00 ButylatedHydroxyanisole 0.5 Butylated Hydroxytoluene 0.36 Polyethylene Oxide(Polyox WSR N80) 123.40 Polyethylene Oxide (Polyox WSR Coagulant) 68.63Hypromellose 2910 (MethocelTM E5 Premium) 50.44 Sodium Chloride 30.22FD&C Red No. 40¹ 0.32 Magnesium Stearate 0.70 Cellulose Acetate (398-10)27.03 Cellulose Acetate (CA 320S) 3.02 Polyethylene Glycol 3350 3.02Hydroxypropyl Cellulose 9.2 Opadry ® II 85F175047 Grey — Opadry ® II85F99094 Blue 9.87 Opadry ® II 85F100129 Purple — Ink, Black (Opacode ®Black S-1-17823) n.a. Purified Water² n.a. Acetone² n.a. Ethanol² n.a.Isopropyl Alcohol² n.a. Total 338.7 ¹FD&C Red No. 40 is listed in FDA'sInactive Ingredients Database and is within the recommended limit.²Water, Acetone, Ethanol and Isopropyl Alcohol are used to manufacturethe tablets but are removed during processing.

TABLE 14 Component Amount (mg) Deutetrabenazine (micronized) 6.00Butylated Hydroxyanisole, NF 1.00 Butylated Hydroxytoluene, NF 0.40Polyethylene Oxide, NF (Polyox ® WSR N80) 137.4 Polyethylene Oxide, NF(FP) (Polyox ® WSR 68.63 Coagulant, Fine Powder) Methocel ® E5 Premium(Hypromellose 2910, USP) 30.25 Sodium Chloride, USP (Powder) 30.22 FD&CRed No. 40 Aluminum Lake HT 38%-42% 0.32 Magnesium Stearate, NF 0.72Cellulose Acetate, NF (398-10) 23.8 Cellulose Acetate, NF (CA 320S) 2.66Polyethylene Glycol 3350, NF 2.66 Hydroxypropyl Cellulose (Klucel ® LF)9.2 Polysorbate 80 NF 4 Opadry ® II Gray 85F97586 9.6 Purified Water,USP n.a. Acetone n.a. Alcohol, USP (Ethyl Alcohol 190 proof) n.a. Total326.8

TABLE 15 Component Amount (mg) Deutetrabenazine 6.00 ButylatedHydroxyanisole 0.5 Butylated Hydroxytoluene 0.36 Polyethylene Oxide(Polyox WSR N80) 123.40 Polyethylene Oxide (Polyox WSR Coagulant) 68.63Hypromellose 2910 (MethocelTM E5 Premium) 54.74 Sodium Chloride 30.22FD&C Red No. 40¹ 0.32 Magnesium Stearate 0.70 Cellulose Acetate (398-10)27.03 Cellulose Acetate (CA 320S) 3.02 Polyethylene Glycol 3350 3.02Hydroxypropyl Cellulose 9.2 Opadry ® II 85F175047 Grey 9.53 Opadry ® II85F99094 Blue — Opadry ® II 85F100129 Purple — Ink. Black (Opacode ®Black S-1-17823) n.a. Purified Water² n.a. Acetone² n.a. Ethanol² n.a.Isopropyl Alcohol² n.a. Total 337.0

Example 2— Single Dose Bioavailability Assessment

Osmotic dosage forms containing 24 mg deutetrabenazine were produced asdisclosed in Example 1 and studied in a single dose pharmacokineticstudy.

The primary objective was to assess the comparative bioavailability (BA)of deutetrabenazine and deuterated α- and β-dihydrotetrabenazine(deuHTBZ) metabolites following a single administration of 24 mg, oncedaily (q.d.) osmotic formulation (Test) compared to a single 12 mgAUSTEDO® tablet administered twice, 12 hours apart (b.i.d), under fastedconditions.

Study Population and Number of Subjects: The study included healthy maleand female non-smoking subjects, aged 18 through 45 years. A total of 8healthy subjects (4 per sequence) were enrolled in this study.

Duration of Subject Participation: The study included a screening periodof 4 weeks (period 1), an open label treatment period with the testformulation (Test2A) and the reference formulation (R) (period 2), and afollow-up visit at least 1 day later (period 3).

Treatments:

Treatment Sequence A:

Day 1—administration of Test2A.

Days 2-3—at least 6 hours wash out of Test2A followed by administrationof R.

Treatment Sequence B:

Day 1—administration of R

Days 2-3—at least 6 hours wash out of R, followed by administration ofTest2A.

The primary objective was addressed using the following parameters:

-   -   maximum observed concentration (C_(max))    -   area under the plasma concentration-time (AUC) from time 0 to        the time of the last measurable plasma concentration (AUC0-t)    -   AUC extrapolated to infinity (AUC0-∞)    -   AUC from time 0 to 24 hours post dose (AUC0-24h)

Analyses

AUC0-t, AUC0-∞, and AUC0-24h were calculated using the trapezoidal rule.The C_(max), AUC0-t, AUC0-∞, and AUC0-24h data was naturallog-transformed prior to the statistical analysis. Comparisons ofC_(max), AUC0-t, AUC0-∞, and AUC0-24h between treatments (T2A vs R) wasbe carried out using a separate parametric analysis of variance (ANOVA)model with fixed effect terms for sequence, period, treatment group, anda random effect of subject within sequence. The difference between thereference formulation (R) and the test formulation (Test2A) wasevaluated by constructing 90% confidence intervals for theTest/Reference ratios, based on the least-square means from the ANOVAfor the log-transformed C_(max), AUC0-t, AUC0-∞ and AUC0-24h. Thetreatment difference and the associated 90% confidence intervalestimated from the ANOVA on the log scale was back-transformed to obtainthe estimated ratio of geometric means between treatment groups and the90% confidence interval for this ratio.

FIG. 3a and FIG. 3b show the results of the R treatment compared toTest2A treatment (mean concentration of deutetrabenazine vs. time)direct scale and log scale, respectively. Table 14, below, provides thespecified pK parameters observed for deutetrabenazine with respect toTest2A compared to R.

TABLE 14 90% C.I. Geometric of Geo- LS Mean metric LS Geometric RatioMean Ratio Compar- pK LS Mean (Test2A/R (Test2A/R) ison Parameter Test2AR (%) (%) Test2A AUC 0-24 h 873.3 898.1 97.2 (78.8, 119.9) vs. R(h*pg/mL) AUC Infinity 1656 1433.7 115.5 (94.6, 141.0) Obs (h*pg/mL)AUC[0-t] 1492.8 1287.4 115.9 (94.2, 142.7) (h*pg/mL) Max Conc 97.7 13771.3 (55.0, 92.5)  (pg/mL)

FIG. 4a and FIG. 4b show the metabolite data for the treatment using Rcompared to Test2A (mean concentration of total deuHTBZ vs. time),direct scale and log scale, respectively.

Table 15, below, provides the specified pK parameters observed for totaldeuHTBZ for the Test2A compared to R.

TABLE 15 Geometric LS Mean 90% C.I. of Test2A R Geometric LS GeometricLS (total (total Mean Ratio Mean Ratio Comparison pK Parameter deuHTBZ)deuHTBZ) (Test2A/R) (%) (Test2A/R) (%) Test2A vs. R AUC 0-24 h 267927.4326315.1 82.1 (77.3, 87.3) (h*pg/mL) AUC Infinity 466549.9 504708.5 92.4(86.0, 99.3) Obs (h*pg/mL) AUC[0-t] 457030.3 495271.0 92.3 (85.9, 99.2)(h*pg/mL) Max Conc 14748.2 29180.0 50.5 (47.0, 54.4) (pg/mL)

As shown in Tables 14 and 15, a once-daily dose of Test2A providedacceptable deuHTBZ plasma concentrations observed for the reference. Theosmotic dosage forms disclosed herein are administered once daily andprovide acceptable treatment effects to that of AUSTEDO® and also haveno safety concerns.

The results of this study, having a crossover design, further show thata patient can be safely and effectively transitioned from a twice daily(two divided doses) administration of deutetrabenazine tablets, to aonce daily osmotic dosage form. The results of this study, having acrossover design, also show that a patient can be safely and effectivelytransitioned from a once daily osmotic dosage form to a twice dailyadministration of deutetrabenazine tablet (two divided doses).

Example 3— Multiple Dose Bioavailability Assessment

Osmotic dosage form containing 24 mg of deutetrabenazine were producedas disclosed in Example 1 and studied in an open label, randomized,multiple-dose, 2-way crossover study in healthy volunteers.

The primary objective was to assess the bioequivalence (BE) ofadministration of Test2A, once daily (qd) compared to bid administrationof R, under fasted or fed conditions.

Treatment included 7 days repeated dosing of Test2A once daily versus 7days repeated dosing of R, bid.

Qualified models were used to predict the steady state, AUCt, C_(max),tmax, Cmin, Cav for deutetrabenazine and deuHTBZ concentrations.

Table 16, below, provides simulation results for steady state pKparameters for deutetrabenazine with respect to Test2A compared to R aswell as pK parameters for total deuHTBZ for the Test2A compared to R.

TABLE 16 PK Compar- Parameter Test2A/R Analyte ison (Mean) Test2A RRatio Deutetra- Test2A AUC_(0-24 h) 2390 1784 1.34 benazine vs. R[pg*h/mL] Deutetra- Test2A C_(max) [pg/mL] 155 134 1.16 benazine vs. RTotal Test2A AUC_(0-24 h) 556826 519835 1.07 deuHTBZ vs. R [pg*h/mL]Total Test2A C_(max) [pg/mL] 28695 28485 1.01 deuHTBZ vs. R

Study Results

Administration of the treatments, Test2A and R, resulted in reproducibleconcentration-time profiles for all analytes.

The primary objective of demonstrating bioequivalence (BE) forAUC_(0-24h,ss) for deutetrabenazine and the deuHTBZ (individually and asa sum) between Test2A and R formulations was met. The geometric LS meanratio for AUC_(0-24h,ss) was 115.15% for deutetrabenazine and 95.05% fortotal deuHTBZ.

The results of this study, having a crossover design, further show thata patient can be safely and effectively transitioned from a twice dailyadministration of deutetrabenazine tablet, to a once daily osmoticdosage form. The results of this study, having a crossover design,further show that a patient can be safely and effectively transitionedfrom a once daily osmotic dosage form to a twice daily administration ofdeutetrabenazine tablet.

Example 4: Food Effect Study

Osmotic dosage forms containing 24 mg deutetrabenazine were produced asdisclosed in Example 1 and studied in an open label, randomized,3-period, 3-treatment, 6-sequence, crossover study, to assess thecomparative bioavailability of deutetrabenazine and deuHTBZ in the fedcompared to the fasted state, following a single administration of 24mg, once daily (qd) osmotic formulation.

Treatment included:

Subjects were randomly assigned to receive 3 treatments: Test2A in fedstate (QD fed), Test2A in the fasted state (QD fasted), and R, 12 hoursapart in fed state [twice daily (BID) fed] in 1 of 6 treatmentsequences, as depicted in FIG. 5.

There was at least a 6-day washout period between the firstadministration in a period and the first administration in the followingperiod. Treatments were orally administered to subjects, in a seatedposition, in the morning on the first day (day 1) of each administrationperiod. The second dose of R in the BID fed group was administeredexactly 12 hours after the morning dose.

All subjects fasted overnight for at least 10 hours before the firstdose during each period. A standardized high-calorie, high-fat breakfast(containing 800 to 1000 kilocalories [kcal] with 50% fat) was served 30minutes before the first dose to subjects receiving R BID fed or Test2Atablet fed. A standardized dinner was served 30 minutes before thesecond dose for R BID fed or the corresponding time for Test2A tabletfed.

Blood samples for pharmacokinetic analysis were collected prior todosing and up to 96 hours after dosing in all treatment periods

AUCt, C_(max), tmax, Cmin, Cav for deutetrabenazine and deuHTBZ wereanalyzed.

Results

For all analytes, variability for the Test2A fed treatment was overallsimilar to that of the Test2A fasted treatment, indicating thatadministration of a single 24 mg tablet in the fed state, as opposed toa single 24 mg tablet in the fasted state, does not greatly increase thepharmacokinetic variability for the metabolites

Following oral administration of a single 24 mg QD osmotic tablet underfed and fasted conditions, all analytes met the BE criteria. Nosignificant food effect on PK was evident, and the 24 mg QD tablet canthus be administered with or without food.

A single dose of 24 mg deutetrabenazine QD osmotic tablet in either thefed or fasted state, as well the 12 mg deutetrabenazine tablet (fedstate) administered twice daily, appeared safe and well tolerated inhealthy subjects.

What is claimed:
 1. A method of transitioning a human subject beingtreated with a total daily dose of deutetrabenazine twice daily (bid) tothe total daily dose as a deutetrabenazine once daily for control ofabnormal involuntary movement, comprising: a) administering to the humansubject a last dose of the deutetrabenazine twice daily; and b) the nextday, administering to the human subject the total daily dose as adeutetrabenazine once daily.
 2. The method of claim 1, wherein the totaldaily dose of deutetrabenazine is from 12 mg to 48 mg; or 12 mg; or 18mg; or 24 mg; or 30 mg; or 36 mg; or 42 mg; or 48 mg.
 3. The method ofclaim 1, wherein the deutetrabenazine once daily is administered as anextended-release osmotic dosage form.
 4. The method of claim 3, whereinthe osmotic dosage form comprises: a. a tablet core comprising an activelayer and a push layer, wherein the active layer comprises an amount ofdeutetrabenazine microparticles and an active layer control releaseagent, and wherein the push layer comprises an osmotic agent and a pushlayer control release agent, and an optional tablet seal coat on theouter surface of the tablet core; b. a semipermeable layer surroundingthe tablet core; c. a port extending through the semipermeable layerinto the tablet core; and d. an optional immediate release coatingexternal to the semipermeable layer comprising a second amount ofdeutetrabenazine microparticles.
 5. The method of claim 4, wherein about70%-80% of the total amount of deutetrabenazine microparticles presentin the osmotic dosage form is present within the active layer andwherein about 20%-30% of the total amount of deutetrabenazinemicroparticles present in the osmotic dosage form, is present within theimmediate release coating.
 6. The method of claim 1, wherein thedeutetrabenazine microparticles have a particle size with a D₉₀ of 15μm, a D₅₀ 10 μm, and/or a D₁₀ of 3 μm.
 7. The method of claim 1, whereinthe abnormal involuntary movement is chorea, akathisia, dyskinesia,tremor, tic, chorea associated with Huntington's disease, tardivedyskinesia, a tic associated with Tourette syndrome, Parkinson's diseaselevodopa-induced dyskinesia, or dyskinesia in cerebral palsy.
 8. Themethod of claim 1, wherein the total daily dose of deutetrabenazine oncedaily is administered with or without food.
 9. A method of transitioninga human subject being treated with a total daily dose ofdeutetrabenazine once daily to the same total daily dose ofdeutetrabenazine twice daily (bid) for control of abnormal involuntarymovement, comprising: a) administering a last dose of thedeutetrabenazine once daily; and b) the next day, administering to thesubject the total daily dose of deutetrabenazine twice daily.
 10. Themethod of claim 9, wherein the total daily dose of deutetrabenazine isfrom 12 mg to 48 mg; or 12 mg; or 18 mg; or 24 mg; or 30 mg; or 36 mg;or 42 mg; or 48 mg.
 11. The method of claim 9, wherein the once dailydose of deutetrabenazine is administered as an extended-release osmoticdosage form.
 12. The method of claim 11, wherein the osmotic dosage formcomprises: a. a tablet core comprising an active layer and a push layer,wherein the active layer comprises an amount of deutetrabenazinemicroparticles and an active layer control release agent, and whereinthe push layer comprises an osmotic agent and a push layer controlrelease agent, and an optional tablet seal coat on the outer surface ofthe tablet core; b. a semipermeable layer surrounding the tablet core;c. a port extending through the semipermeable layer into the tabletcore; and d. an optional immediate release coating external to thesemipermeable layer comprising a second amount of deutetrabenazinemicroparticles.
 13. The method of claim 12, wherein about 70%-80% of thetotal amount of deutetrabenazine microparticles present in the osmoticdosage form is present within the active layer and wherein about 20%-30%of the total amount of deutetrabenazine microparticles present in theosmotic dosage form, is present within the immediate release coating.14. The method of claim 12, wherein the deutetrabenazine microparticleshave a particle size with a D₉₀ of 15 μm, a D₅₀ 10 μm, and/or a D₁₀ of 3μm.
 15. The method of claim 9, wherein the abnormal involuntary movementis chorea, akathisia, dyskinesia, tremor, tic, chorea associated withHuntington's disease, tardive dyskinesia, a tic associated with Tourettesyndrome, Parkinson's disease levodopa-induced dyskinesia or dyskinesiain cerebral palsy.
 16. The method of claim 9, wherein the total dailydose of once daily deutetrabenazine is administered with or withoutfood.
 17. A method of transitioning a human subject being treated with adaily amount of tetrabenazine to a once daily amount ofdeutetrabenazine, for control of abnormal involuntary movement from,comprising: a) administering the last dose of tetrabenazine; and b) thenext day, administering to the subject a once daily deutetrabenazineosmotic dosage form wherein: the daily amount of tetrabenazine is 12.5mg and the once daily amount of deutetrabenazine is 6 mg; or wherein thedaily amount of tetrabenazine is 25 mg and the once daily amount ofdeutetrabenazine is 12 mg; or wherein the daily amount of tetrabenazineis 37.5 mg and the once daily amount of deutetrabenazine is 18 mg; orwherein the daily amount of tetrabenazine is 50 mg and the once dailyamount of deutetrabenazine is 24 mg; or wherein the daily amount oftetrabenazine is 62.5 mg and the once daily amount of deutetrabenazineis 30 mg; or wherein the daily amount of tetrabenazine is 75 mg and theonce daily amount of deutetrabenazine is 36 mg; or wherein the dailyamount of tetrabenazine is 87.5 mg and the once daily amount ofdeutetrabenazine is 42 mg; or wherein the daily amount of tetrabenazineis 100 mg and the once daily amount of deutetrabenazine is 48 mg; andwherein the osmotic dosage form comprises: a. a tablet core comprisingan active layer and a push layer, wherein the active layer comprises anamount of deutetrabenazine microparticles and an active layer controlrelease agent, and wherein the push layer comprises an osmotic agent anda push layer control release agent, and an optional tablet seal coat onthe outer surface of the tablet core; b. a semipermeable layersurrounding the tablet core; c. a port extending through thesemipermeable layer into the tablet core; and d. an optional immediaterelease coating external to the semipermeable layer comprising a secondamount of deutetrabenazine microparticles.
 18. The method of claim 17,wherein about 70%-80% of the total amount of deutetrabenazinemicroparticles present in the osmotic dosage form is present within theactive layer and wherein about 20%-30% of the total amount ofdeutetrabenazine microparticles present in the osmotic dosage form, ispresent within the immediate release coating.
 19. The method of claim17, wherein the deutetrabenazine microparticles have a particle sizewith a D₉₀ of 15 μm, a D₅₀ 10 μm, and/or a D₁₀ of 3 μm.
 20. The methodof claim 17, wherein the abnormal involuntary movement is chorea,akathisia, dyskinesia, tremor, tic, chorea associated with Huntington'sdisease, tardive dyskinesia, a tic associated with Tourette syndrome,Parkinson's disease levodopa-induced dyskinesia or dyskinesia incerebral palsy.
 21. The method of claim 17, wherein the once dailydeutetrabenazine dosage form, is administered with or without food.